Antimicrobials and methods of making and using same

ABSTRACT

The present disclosure relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, reducing the risk of, and delaying the onset of microbial infections in humans and animals. In some embodiments, the present disclosure provides a compound of Formula (I): or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application SerialNos. 62/444,291, filed Jan. 9, 2017; and 62/333,026, filed May 6, 2016,all of which are herein incorporated by reference in their entireties.

TECHNICAL FIELD

This invention relates to antimicrobial compounds, and more particularlyto pyrrolo[2,3-d]pyrimidin-2-ones useful for treating, preventing andreducing risk of microbial infections.

BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the1940s, many new compounds have been discovered or specifically designedfor use as antibiotic agents. It was once thought that infectiousdiseases could be completely controlled or eradicated with the use ofsuch therapeutic agents. However, such views have been challengedbecause strains of cells or microorganisms resistant to currentlyeffective therapeutic agents continue to evolve. Almost every antibioticagent developed for clinical use has ultimately encountered problemswith the emergence of resistant bacteria. For example, resistant strainsof Gram-positive bacteria such as methicillin-resistant staphylococci,penicillin-resistant streptococci, and vancomycin-resistant enterococcihave developed. Resistant bacteria can cause serious and even fatalresults for infected patients. See, e.g., Lowry, F. D. “AntimicrobialResistance: The Example of Staphylococcus aureus,” J. Clin. Invest.,vol. 111, no. 9, pp. 1265-1273 (2003); and Gold, H. S. and Moellering,R. C., Jr., “Antimicrobial-Drug Resistance,” N. Engl. J. Med., vol. 335,pp. 1445-53 (1996).

The discovery and development of new antibacterial agents have been fordecades a major focus of many pharmaceutical companies. Nonetheless, inmore recent years there has been an exodus from this area of researchand drug development resulting in very few new antibiotics entering themarket. This lack of new antibiotics is particularly disturbing,especially at a time when bacterial resistance to current therapies isincreasing both in the hospital and community settings.

One approach to developing new antimicrobial compounds is to designmodulators, for example, inhibitors, of bacterial ribosome function. Bymodulating or inhibiting bacterial ribosome function, antimicrobialcompounds could interfere with essential processes such as RNAtranslation and protein synthesis, thereby providing an antimicrobialeffect. In fact, some antibiotic compounds such as erythromycin,clindamycin, and linezolid are known to bind to the ribosome.

SUMMARY

The present disclosure relates generally to the field of antimicrobialcompounds and to methods of making and using them. These compounds andtautomers thereof are useful for treating, preventing, reducing the riskof, or delaying the onset of microbial infections in humans and animals.The present disclosure also provides pharmaceutically acceptable saltsof these compounds and tautomers.

In some embodiments, provided herein is a compound of Formula (I)

or a tautomer or a pharmaceutically acceptable salt of the compound ortautomer, wherein:

R₁ is halo;

R₂ is halo;

R₃ is selected from H, halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1),S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl, wherein the C₁₋₆alkyl is optionally substituted with a substituent selected fromC(O)OR^(a1), C(O)NR^(c1)R^(d1), _(an)d C₁₋₄ alkoxy, and wherein the C₁₋₄alkoxy is optionally substituted with C₁₋₄ alkoxy;

R₄ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl is optionally substituted with a substituent selected fromOR^(a2), SR^(a2), NR^(c2)R^(d2), and NR^(c2)C(═NR^(e2))NR^(c2)R^(d2);

X is selected from O, NRs₅, and CH₂;

R₅ is selected from H and C₁₋₄ alkyl;

W is selected from CR^(6A)R^(6B) and NR^(6A);

Y is N or CR₃;

R^(6A) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R^(6B) is H; or

R^(6A) and R^(6B) together form an oxo group; or

R^(6A) and R₄ together with the carbon atom to which R₄ is attached, theW atom to which R^(6A) is attached and the X atom connecting W and thecarbon atom to which R₄ is attached, form a 5- to 6-memberedheterocycloalkyl ring containing 1-3 heteroatoms;

R₇ is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₅ cycloalkyl;

each of R^(a1), R^(b1), R^(c1), R_(d1), R^(a2), R^(c2), and R^(d2) isindependently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and 5- to6-membered heteroaryl; and

R₈ is selected from H, C₁₋₄ alkenyl, C₁₋₄ haloalkyl and C₋₄ alkyloptionally substituted with a substituent selected from amino, C₁₋₄alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-membered heterocycloalkyl;

R₉ is selected from H and halo; and

R^(e2) is selected from H and C₁₋₄ alkyl.

In some embodiments, provided herein is a compound of Formula (II):

or a tautomer or a pharmaceutically acceptable salt of the compound ortautomer, wherein:

R₁ is halo;

R₂ is halo;

R₃ is selected from H, halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1),SR^(a1), S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromC(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄alkoxy is optionally substituted with C₁₋₄ alkoxy;

R₄ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl is optionally substituted with a substituent selected fromOR^(a2), SR^(a2), NR^(c2)R^(d2), and NR^(c2)C(═NR^(e2))NR^(c2)R^(d2);

X is selected from O, NR₅, and CH₂;

R₅ is selected from H and C₁₋₄ alkyl;

W is selected from CR^(6A)R^(6B) and NR^(6A);

Y is N or CR₃;

R^(6A) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R^(6B) is H; or

R^(6A) and R^(6B) together form an oxo group; or

R^(6A) and R₄ together with the carbon atom to which R₄ is attached, theW atom to which R^(6A) is attached and the X atom connecting W and thecarbon atom to which R₄ is attached, form a 5- to 6-memberedheterocycloalkyl ring containing 1-3 heteroatoms;

R₇ is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₅ cycloalkyl;

each of R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(c2), and R^(d2) isindependently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and 5- to6-membered heteroaryl; and

R₈ is selected from H, C₁₋₄ alkenyl, C₁₋₄ haloalkyl and C₁₋₄ alkyloptionally substituted with a substituent selected from amino, C₁₋₄alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-membered heterocycloalkyl; and

R^(c2) is selected from H and C₁₋₄ alkyl.

In some embodiments provided herein is a pharmaceutical compositioncomprising a compound of Formula (I) or Formula (II), or a tautomerthereof or a pharmaceutically acceptable salt of the compound ortautomer, and a pharmaceutically acceptable carrier.

In some embodiments provided herein is a method of treating a microbialinfection comprising administering to a subject in need thereof aneffective amount of a compound of Formula (I) or Formula (II), or atautomer thereof or a pharmaceutically acceptable salt of the compoundor tautomer, or a pharmaceutically acceptable composition as providedherein.

In some embodiments provided herein is a method of preventing amicrobial infection comprising administering to a subject in needthereof an effective amount of a compound of Formula (I) or Formula(II), or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, or a pharmaceutically acceptable composition asprovided herein.

In some embodiments provided herein is a method of reducing the risk ofa microbial infection comprising administering to a subject in needthereof an effective amount of a compound of Formula (I) or Formula(II), or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, or a pharmaceutically acceptable composition asprovided herein.

In some embodiments provided herein is a method of delaying the onset ofa microbial infection comprising administering to a subject in needthereof an effective amount of a compound of Formula (I) or Formula(II), or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, or a pharmaceutically acceptable composition asprovided herein.

In some embodiments provided herein is a method of treating a microbialinfection comprising administering to a subject in need thereof aneffective amount of a compound of Formula (I) or Formula (II), or atautomer thereof or a pharmaceutically acceptable salt of the compoundor tautomer, or a pharmaceutically acceptable composition as providedherein.

In some embodiments provided herein is a use of a compound of Formula(I) or Formula (II), or a tautomer thereof or a pharmaceuticallyacceptable salt of the compound or tautomer, in the manufacture of amedicament for treating, preventing, or reducing a microbial infectionin a subject.

In some embodiments provided herein is a compound of Formula (I) or

Formula (II), or a tautomer thereof or a pharmaceutically acceptablesalt of the compound or tautomer, for use in treating, preventing, orreducing a microbial infection in a subject.

In addition, the disclosure provides methods of synthesizing theforegoing compounds and tautomers thereof, and pharmaceuticallyacceptable salts of said compounds and tautomers. Following synthesis,an effective amount of one or more of the compounds or tautomersthereof, or pharmaceutically acceptable salts of said compounds ortautomers can be formulated with a pharmaceutically acceptable carrierfor administration to a human or animal for use as antimicrobial agents,particularly as antibacterial agents. In certain embodiments, thecompounds of the present disclosure are useful for treating, preventing,reducing the risk of, or delaying the onset of microbial infections orfor the manufacture of a medicament for treating, preventing, reducingthe risk of, or delaying the onset of microbial infections.

Accordingly, the compounds or tautomers thereof, or pharmaceuticallyacceptable salts of said compounds or tautomers or their formulationscan be administered, for example, via oral, parenteral, intravenous,otic, ophthalmic, nasal, or topical routes, to provide an effectiveamount of the compound or tautomer thereof, or pharmaceuticallyacceptable salt of said compound or tautomer to the human or animal.

The foregoing and other aspects and embodiments of the disclosure can bemore fully understood by reference to the following detailed descriptionand claims.

DETAILED DESCRIPTION

The present disclosure utilizes a structure based drug design approachfor discovering and developing new antimicrobial agents. This approachstarts with a high resolution X-ray crystal of a ribosome to design newclasses of antimicrobial compounds having specific chemical structures,ribosome binding characteristics, and antimicrobial activity. Thisstructure based drug discovery approach is described in the followingpublication: Franceschi, F. and Duffy, E. M., “Structure-based drugdesign meets the ribosome”, Biochemical Pharmacology, vol. 71, pp.1016-1025 (2006).

Based on this structure based drug design approach, the presentdisclosure describes new chemical classes of antimicrobial compoundsuseful for treating bacterial infections in humans and animals. Withoutbeing limited by theories, these compounds are believed to inhibitbacterial ribosome function by binding to the ribosome. By takingadvantage of these ribosome binding sites, the antimicrobial compoundsof the present disclosure can provide better activity, especiallyagainst resistant strains of bacteria, than currently availableantibiotic compounds.

The present disclosure therefore fills an important ongoing need for newantimicrobial agents, particularly for antimicrobial agents, havingactivity against resistant pathogenic bacterial organisms.

The present disclosure provides a family of compounds or tautomersthereof, that can be used as antimicrobial agents, more particularly asantibacterial agents.

The present disclosure also includes pharmaceutically acceptable saltsof said compounds and tautomers.

The compounds or tautomers thereof, or pharmaceutically acceptable saltsof said compounds or tautomers disclosed herein can have asymmetriccenters. Compounds or tautomers thereof, or pharmaceutically acceptablesalts of said compounds or tautomers of the present disclosurecontaining an asymmetrically substituted atom can be isolated inoptically active or racemic forms. It is well known in the art how toprepare optically active forms, such as by resolution of racemic formsor by synthesis from optically active starting materials. Many geometricisomers of olefins, C═N double bonds, and the like can also be presentin the compounds or tautomers thereof, or pharmaceutically acceptablesalts of said compounds or tautomers disclosed herein, and all suchstable isomers are contemplated in the present disclosure. Cis and transgeometric isomers of the compounds or tautomers thereof, orpharmaceutically acceptable salts of said compounds or tautomers of thepresent disclosure are described and can be isolated as a mixture ofisomers or as separate isomeric forms. All chiral, diastereomeric,racemic, and geometric isomeric forms of a structure are intended,unless specific stereochemistry or isomeric form is specificallyindicated. All processes used to prepare compounds or tautomers thereof,or pharmaceutically acceptable salts of said compounds or tautomers ofthe present disclosure and intermediates made herein are considered tobe part of the present disclosure. All tautomers of shown or describedcompounds are also considered to be part of the present disclosure.Furthermore, the disclosure also includes metabolites of the compoundsdisclosed herein.

The disclosure also comprehends isotopically-labeled compounds ortautomers thereof, or pharmaceutically acceptable salts of saidcompounds or tautomers, which are identical to those recited in formulaeof the disclosure, but for the replacement of one or more atoms by anatom having an atomic mass or mass number different from the atomic massor mass number most commonly found in nature. Examples of isotopes thatcan be incorporated into compounds or tautomers thereof, orpharmaceutically acceptable salts of said compounds or tautomers of thedisclosure and include isotopes of hydrogen, carbon, nitrogen, andfluorine, such as ³H, ¹¹C, ¹⁴C, and ¹⁸F.

The compounds of the present disclosure or tautomers thereof, orpharmaceutically acceptable salts of said compounds or tautomers thatcontain the aforementioned isotopes and/or isotopes of other atoms arewithin the scope of the present disclosure. Isotopically-labeledcompounds or tautomers thereof, or pharmaceutically acceptable salts ofsaid compounds or tautomers of the present disclosure, for example,those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritium, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred due to their ease of preparation anddetectability. ₁₁C and ¹⁸F isotopes are particularly useful in PET(positron emission tomography). PET is useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, i.e., increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds or tautomers thereof, or pharmaceuticallyacceptable salts of said compounds or tautomers having a formula of thedisclosed herein can generally be prepared as described in theprocedures, Schemes and/or in the Examples disclosed herein, bysubstituting a non-isotopically labeled reagent with a readily availableisotopically labeled reagent. In one embodiment, the compounds ortautomers thereof, or pharmaceutically acceptable salts of saidcompounds or tautomers disclosed herein are not isotopically labeled.

When any variable (e.g., R) occurs more than one time in any constituentor formulae of the disclosed herein, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more Rmoieties, then R at each occurrence is selected independently from thedefinition of R. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compoundswithin a designated atom's normal valence.

A chemical structure showing a dotted line representation for a chemicalbond indicates that the bond is optionally present. For example, adotted line drawn next to a solid single bond indicates that the bondcan be either a single bond or a double bond.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent can be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent can be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

In cases wherein compounds of the present disclosure, or tautomersthereof, or pharmaceutically acceptable salts of said compounds ortautomers thereof, contain nitrogen atoms, these, where appropriate, canbe converted to N-oxides by treatment with an oxidizing agent (e.g.,meta-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides). Thus,shown and claimed nitrogen atoms are considered to cover both the shownnitrogen and its N-oxide (N-→O) derivative, as appropriate. In someembodiments, the present disclosure relates to N-oxides of the compoundsor tautomers thereof, or pharmaceutically acceptable salts of saidcompounds or tautomers disclosed herein.

One approach to developing improved anti-proliferative andanti-infective agents is to provide modulators (for example, inhibitors)of ribosome function.

Ribosomes are ribonucleoproteins, which are present in both prokaryotesand eukaryotes. Ribosomes are the cellular organelles responsible forprotein synthesis. During gene expression, ribosomes translate thegenetic information encoded in a messenger RNA into protein (Garrett etal. (2000) “The Ribosome: Structure, Function, Antibiotics and CellularInteractions,” American Society for Microbiology, Washington, D.C.).

Ribosomes comprise two nonequivalent ribonucleoprotein subunits. Thelarger subunit (also known as the “large ribosomal subunit”) is abouttwice the size of the smaller subunit (also known as the “smallribosomal subunit”). The small ribosomal subunit binds messenger RNA(mRNA) and mediates the interactions between mRNA and transfer RNA(tRNA) anticodons on which the fidelity of translation depends. Thelarge ribosomal subunit catalyzes peptide bond formation, i.e., thepeptidyl-transferase reaction of protein synthesis, and includes, atleast, three different tRNA binding sites known as the aminoacyl,peptidyl, and exit sites. The aminoacyl site or A-site accommodates theincoming aminoacyl-tRNA that is to contribute its amino acid to thegrowing peptide chain. Also, the A space of the A-site is important. Thepeptidyl site or P-site accommodates the peptidyl-tRNA complex, i.e.,the tRNA with its amino acid that is part of the growing peptide chain.The exit or E-site accommodates the deacylated tRNA after it has donatedits amino acid to the growing polypeptide chain.

1. Definitions

“Isomerism” means compounds that have identical molecular formulae butthat differ in the nature or the sequence of bonding of their atoms orin the arrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

“Chiral isomer” means a compound with at least one chiral center. Acompound with one chiral center has two enantiomeric forms of oppositechirality and may exist either as an individual enantiomer or as amixture of enantiomers. A mixture containing equal amounts of individualenantiomeric forms of opposite chirality is termed a “racemic mixture”.A compound that has more than one chiral center has 2^(n-1) enantiomericpairs, where n is the number of chiral centers. Compounds with more thanone chiral center may exist as either an individual diastereomer or as amixture of diastereomers, termed a “diastereomeric mixture”. When onechiral center is present, a stereoisomer may be characterized by theabsolute configuration (R or S) of that chiral center. Absoluteconfiguration refers to the arrangement in space of the substituentsattached to the chiral center. The substituents attached to the chiralcenter under consideration are ranked in accordance with the SequenceRule of Cahn, Ingold and Prelog. (Cahn et al, Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahnand Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia1956, 12, 81; Cahn, J., Chem. Educ. 1964, 41, 116).

“Geometric Isomers” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Further, the compounds discussed in this application include all atropicisomers thereof. “Atropic isomers” are a type of stereoisomer in whichthe atoms of two isomers are arranged differently in space. Atropicisomers owe their existence to a restricted rotation caused by hindranceof rotation of large groups about a central bond. Such atropic isomerstypically exist as a mixture, however, as a result of recent advances inchromatography techniques, it has been possible to separate mixtures oftwo atropic isomers in select cases.

Some compounds of the present disclosure can exist in a tautomeric formwhich is also intended to be encompassed within the scope of the presentdisclosure. “Tautomers” refers to compounds whose structures differmarkedly in the arrangement of atoms, but which exist in easy and rapidequilibrium. It is to be understood that compounds of present disclosuremay be depicted as different tautomers. It should also be understoodthat when compounds have tautomeric forms, all tautomeric forms areintended to be within the scope of the disclosure, and the naming of thecompounds does not exclude any tautomeric form.

The compounds and pharmaceutically acceptable salts of the presentdisclosure can exist in one or more tautomeric forms, including the enoland imine form and the keto and enamine form, and geometric isomers andmixtures thereof All such tautomeric forms are included within the scopeof the present disclosure. Tautomers exist as mixtures of a tautomericset in solution. In solid form, usually one tautomer predominates. Eventhough one tautomer may be described, the present disclosure includesall tautomers of the compounds disclosed herein.

A tautomer is one of two or more structural isomers that exist inequilibrium and are readily converted from one isomeric form to another.This reaction results in the formal migration of a hydrogen atomaccompanied by a shift of adjacent conjugated double bonds. In solutionswhere tautomerization is possible, a chemical equilibrium of thetautomers can be reached. The exact ratio of the tautomers depends onseveral factors, including temperature, solvent, and pH. The concept oftautomers that are interconvertible by tautomerizations is calledtautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism, a simultaneous shift of electronsand a hydrogen atom occurs. Ring-chain tautomerism, exhibited by glucoseand other sugars, arises as a result of the aldehyde group (—CHO) in asugar chain molecule reacting with one of the hydroxy groups (—OH) inthe same molecule to give it a cyclic (ring-shaped) form.

Tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formationof a delocalized anion (e.g., an enolate); 3. protonation at a differentposition of the anion; Acid: 1. protonation; 2. formation of adelocalized cation; 3. deprotonation at a different position adjacent tothe cation.

Common tautomeric pairs include: ketone-enol, amide-nitrile,lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings(e.g., in the nucleobases guanine, thymine, and cytosine), amine-enamineand enamine-enamine. Examples below are included for illustrativepurposes, and the present disclosure is not limited to the examples:

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom, usually a carbon, oxygen, or nitrogenatom, is replaced with a selection from the indicated group, providedthat the designated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. When a substituent is keto oroxo (i.e., ═O), then 2 hydrogens on the atom are replaced. Ring doublebonds, as used herein, are double bonds that are formed between twoadjacent ring atoms (e.g., C═C, C═N, N═N, etc.).

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁₋₄ is intended toinclude C₁, C₂, C₃, and C₄. C₁₋₆ alkyl is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkyl groups and C₁₋₈ is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, and C₈. Some examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, and n-octyl.

As used herein, “alkenyl” is intended to include hydrocarbon chains ofeither straight or branched configuration and one or more unsaturatedcarbon-carbon bonds that can occur in any stable point along the chain,such as ethenyl and propenyl. For example, C₂₋₆ alkenyl is intended toinclude C₂, C₃, C₄, C₅, and C₆ alkenyl groups and C₂₋₈ alkenyl isintended to include C₂, C₃, C₄, C₅, C₆, C₇, and C₈.

As used herein, “cycloalkyl” is intended to include saturated orunsaturated nonaromatic ring groups, such as cyclopropyl, cyclobutyl, orcyclopentyl. C₃₋₈ cycloalkyl is intended to include C₃, C₄, C₅, C₆, C₇,and C₈ cycloalkyl groups. Cycloalkyls may include multiple spiro- orfused rings.

As used herein, the term “heterocycloalkyl” refers to a saturated orunsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic(fused, bridged, or spiro rings), or 11-14 membered tricyclic ringsystem (fused, bridged, or spiro rings) having one or more heteroatoms(such as O, N, S, or Se), unless specified otherwise. A heterocycloalkylgroup containing a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6membered heterocycloalkyl having 1 or 2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur and having one or moreoxidized ring members. In some embodiments, the heterocycloalkyl is amonocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or4 heteroatoms independently selected from nitrogen, oxygen, or sulfurand having one or more oxidized ring members. Examples ofheterocycloalkyl groups include, but are not limited to, piperidinyl,piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl,indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxetanyl,thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl,dihydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl,2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl,1,4-dioxa-8-azaspiro[4.5]decanyl and the like.

As used herein, “amine” or “amino” refers to unsubstituted -NH₂ unlessotherwise specified.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo substituents.

As used herein, “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with one or more halogen(for example —C_(v)F_(w)H_(2v−w+1) wherein v=1 to 3 and w=1 to (2v+1)).Examples of haloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. As used herein,“alkoxyl” or “alkoxy” refers to an alkyl group as defined above with theindicated number of carbon atoms attached through an oxygen bridge. C₁₋₆alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups.C₁₋₈ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈alkoxy groups. Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.

As used herein, “aryl” includes groups with aromaticity, including“conjugated,” or multicyclic systems with at least one aromatic ring anddo not contain any heteroatom in the ring structure. Aryl may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m) aryl” refers to an aryl group having from n to m ring carbonatoms. In some embodiments, aryl groups have from 6 to 10 carbon atoms.In some embodiments, the aryl group is phenyl or naphtyl.

As used herein, the term “aromatic heterocycle”, “aromatic heterocyclic”or “heteroaryl” ring is intended to mean a stable 5, 6, 7, 8, 9, 10, 11,or 12-membered monocyclic or bicyclic aromatic ring which consists ofcarbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen,and sulfur. In the case of bicyclic aromatic heterocyclic or heterocycleor heteroaryl rings, only one of the two rings needs to be aromatic(e.g., 2,3-dihydroindole), though both can be (e.g., quinoline). Thesecond ring can also be fused or bridged as defined above forheterocycles. The nitrogen atom can be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, as defined). Thenitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→Oand S(O)_(p), wherein p=1 or 2). In certain compounds, the total numberof S and O atoms in the aromatic heterocycle is not more than 1.

Examples of aromatic heterocycles, aromatic heterocyclics or heteroarylsinclude, but are not limited to acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzooxadiazoly,carbazolyl, 4aH-carbazolyl, carbolinyl, cinnolinyl, furazanyl,imidazolyl, imidazolonyl, 1H-indazolyl, indolizinyl, indolyl,3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, methylbenztriazolyl,methylfuranyl, methylimidazolyl, methylthiazolyl, naphthyridinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazolyl,pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridinonyl, pyridyl,pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, tetrahydroquinolinyl, tetrazolyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, and 1,3,4-triazolyl.

The term “hydroxyalkyl” means an alkyl group as defined above, where thealkyl group is substituted with one or more OH groups. Examples ofhydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond, i.e., C≡N.

As used herein, “oxo” is means a “═O” group.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds or tautomers thereof, or salts thereof, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds or tautomers thereof, wherein the parentcompound or a tautomer thereof, is modified by making of the acid orbase salts thereof of the parent compound or a tautomer thereof.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound, or a tautomer thereof, formed, for example, fromnon-toxic inorganic or organic acids. For example, such conventionalnon-toxic salts include, but are not limited to, those derived frominorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present disclosure can besynthesized from the parent compound or a tautomer thereof, thatcontains a basic or acidic moiety by conventional chemical methods.Generally, such pharmaceutically acceptable salts can be prepared byreacting the free acid or base forms of these compounds or tautomersthereof with a stoichiometric amount of the appropriate base or acid inwater or in an organic solvent, or in a mixture of the two; generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred. Lists of suitable salts are found inington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company,Easton, Pa.USA, p. 1445 (1990).

used herein, “stable compound” and “stable structure” are meant toindicate a compound that is sufficiently robust to survive isolation toa useful degree of purity from a reaction mixture, and formulation intoan efficacious therapeutic agent.

As used herein, the term “treating” means to provide a therapeuticintervention to cure or ameliorate an infection. In some embodiments,“treating” refers to administering a compound or pharmaceuticalcomposition as provided herein for therapeutic purposes. The term“therapeutic treatment” refers to administering treatment to a patientalready suffering from a disease thus causing a therapeuticallybeneficial effect, such as ameliorating existing symptoms, amelioratingthe underlying metabolic causes of symptoms, postponing or preventingthe further development of a disorder, and/or reducing the severity ofsymptoms that will or are expected to develop.

As used herein, the term “preventing”, as used herein means, tocompletely or almost completely stop an infection from occurring, forexample when the patient or subject is predisposed to an infection or atrisk of contracting an infection. Preventing can also includeinhibiting, i.e., arresting the development, of an infection.

As used herein, the term “reducing the risk of”, as used herein, meansto lower the likelihood or probability of an infection occurring, forexample when the patient or subject is predisposed to an infection or atrisk of contracting an infection.

As used herein, “unsaturated” refers to compounds having at least onedegree of unsaturation (e.g., at least one multiple bond) and includespartially and fully unsaturated compounds.

As used herein, the term “effective amount” refers to an amount of acompound or a tautomer thereof, or a pharmaceutically acceptable salt ofsaid compound or tautomer (including combinations of compounds and/ortautomers thereof, and/or pharmaceutically acceptable salts of saidcompound or tautomer) of the present disclosure that is effective whenadministered alone or in combination as an antimicrobial agent. Forexample, an effective amount refers to an amount of the compound ortautomer thereof, or a pharmaceutically acceptable salt said compound ortautomer that is present in a composition, a formulation or on a medicaldevice given to a recipient patient or subject sufficient to elicitbiological activity, for example, anti-infective activity, such as e.g.,anti-microbial activity, anti-bacterial activity, anti-fungal activity,anti-viral activity, or anti-parasitic activity.

The term “prophylactically effective amount” means an amount of acompound or a tautomer of said compound or tautomer, or apharmaceutically acceptable salt of said compound or tautomer (includingcombinations of compounds and/or tautomers thereof, and/orpharmaceutically acceptable salts thereof), of the present disclosurethat is effective prophylactically when administered alone or incombination as an antimicrobial agent. For example, a prophylacticallyeffective amount refers to an amount of the compound or tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer that is present in a composition, a formulation, or on amedical device given to a recipient patient or subject sufficient toprevent or reduce the risk of an infection due to a surgical procedureor an invasive medical procedure.

In the specification, the singular forms also include the plural, unlessthe context clearly dictates otherwise. Unless defined otherwise, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. In the case of conflict, the present specificationwill control. As used herein, “mammal” refers to human and non-humanpatients.

As used herein, the term ESBL is extended spectrum beta-lactamase. Theterm KPC is Klebsiella pneumoniae carbapenemase.

As used herein, the term acute bacterial skin and skin structureinfection (ABSSSI) encompasses complicated skin and skin structureinfections (cSSSI) and complication skin and soft tissue infections(cSSTI), which have been used interchangeably. The terms uncomplicatedskin and skin structure infections (uCSSSI) and uncomplicated skin andsoft tissue infections (uCSSTI) have been used interchangeably.

As used herein, the term “spp.” is the abbreviation for species.

As used herein, the term “formulae of the disclosure” or “formulaedisclosed herein” includes one or more of the Formulae: (I), (Ia), (Ib),(Ic), (Ic-1), (Id), (Ie), (If), (Ig), (Ih), and (Ii).

As used herein, the term “compound of the disclosure” or “compounddisclosed herein” includes one or more compounds of the formulae of thedisclosure or a compound explicitly disclosed herein.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present disclosure also consistessentially of, or consist of, the recited components, and that theprocesses of the present disclosure also consist essentially of, orconsist of, the recited processing steps. Further, it should beunderstood that the order of steps or order for performing certainactions are immaterial so long as the invention remains operable.Moreover, two or more steps or actions can be conducted simultaneously.

2. Compounds of the Disclosure

In some embodiments, the present disclosure provides a compound ofFormula (I)

or a tautomer or a pharmaceutically acceptable salt of the compound ortautomer, wherein:

R₁ is halo;

R₂ is halo;

R₃ is selected from H, halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1),SR^(a1), S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl, wherein theC₋₆ alkyl is optionally substituted with a substituent selected fromC(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄alkoxy is optionally substituted with C₁₋₄ alkoxy;

R₄ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl is optionally substituted with a substituent selected fromOR^(a2), SR^(a2), NR^(c2)R^(d2), and NR^(c2)C(═NR^(e2))NR^(c2)R^(d2);

X is selected from O, NR₅, and CH₂;

R₅ is selected from H and C₁₋₄ alkyl;

W is selected from CR^(6A)R^(6B) and NR^(6A);

Y is N or CR₃;

R^(6A) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R^(6B) is H; or

R^(6A) and R^(6B) together form an oxo group; or

R^(6A) and R₄ together with the carbon atom to which R₄ is attached, theW atom to which R^(6A) is attached and the X atom connecting W and thecarbon atom to which R₄ is attached, form a 5- to 6-memberedheterocycloalkyl ring containing 1-3 heteroatoms;

R₇ is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₅ cycloalkyl;

each of R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(c2), and R^(d2) isindependently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and 5- to6-membered heteroaryl; and

R₈ is selected from H, C₁₋₄ alkenyl, C₁₋₄ haloalkyl and C₁₋₄ alkyloptionally substituted with a substituent selected from amino, C₁₋₄alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-membered heterocycloalkyl;

R₉ is selected from H and halo; and

R^(e2) is selected from H and C₁₋₄ alkyl.

In some embodiments, the present disclosure provides a compound ofFormula

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

R₁ is halo;

R₂ is halo;

R₃ is selected from H, halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1),SR^(a1), S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromC(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄alkoxy is optionally substituted with C₁₋₄ alkoxy;

R₄ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl is optionally substituted with a substituent selected fromOR^(a2), SR^(a2), NR^(c2)R^(d2), and NR^(c2)C(═NR^(e2))NR^(c2)R^(d2);

X is selected from O, NR₅, and CH₂;

R₅ is selected from H and C₁₋₄ alkyl;

W is selected from CR^(6A)R^(6B) and NR^(6A);

Y is selected from N and CR₃;

R^(6A) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R^(6B) is H; or

R^(6A) and R^(6B) together form an oxo group; or

R^(6A) and R₄ together with the carbon atom to which R₄ is attached, theW atom to which R^(6A) is attached and the X atom connecting W and thecarbon atom to which R₄ is attached, form a 5- to 6-memberedheterocycloalkyl ring containing 1-3 heteroatoms;

R₇ is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₅ cycloalkyl;

each R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(c2), and R^(d2) isselected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and 5- to 6-memberedheteroaryl;

R₈ is selected from H, C₁₋₄ alkenyl, C₁₋₄ haloalkyl and C₁₋₄ alkyloptionally substituted with a substituent selected from amino, C₁₋₄alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-membered heterocycloalkyl; and

R^(c2) is selected from H and C₁₋₄ alkyl.

In some embodiments of Formula (I) or Formula (II), R₁ is fluoro. Insome embodiments, R₁ is chloro. In some embodiments, R₁ is bromo oriodo.

In some embodiments, of Formula (I) or Formula (II), R₂ is chloro. Insome embodiments, R₂ is fluoro. In some embodiments, R₂ is bromo oriodo.

In some embodiments, of Formula (I) or Formula (II), R₁ is fluoro and R₂is chloro.

In some embodiments, of Formula (I) or Formula (II), Y is N. In someembodiments, Y is CR₃.

In some embodiments of Formula (I) or Formula (II), R₃ is selected fromhalo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1), S(O)₂R^(b1), and 5- to6-membered heterocycloalkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with a substituent selected from C(O)OR^(a1),C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄ alkoxy isoptionally substituted with C₁₋₄ alkoxy. In some embodiments, R₃ ishalo. In some embodiments, R₃ is C₁₋₆ alkyl. In some embodiments, R₃ isOR^(a1) or SR^(a1). In some embodiments, R₃ is 5- to 6-memberedheterocycloalkyl. In some embodiments, R₃ is selected from H, fluoro,NO₂, methylsulfonyl, methoxy, methylthio, carboxymethyl,methylaminocarbonylmethyl, N-morpholino, (2-methoxyethoxy)methyl, anddimethylamino. In some embodiments, R₃ is selected from fluoro, NO₂,methyl sulfonyl, methoxy, methylthio, carboxymethyl,methylaminocarbonylmethyl, N-morpholino, (2-methoxyethoxy)methyl, anddimethylamino. In some embodiments, R₃ is fluoro. In some embodiments,R₃ is methoxy or methylthio. In some embodiments, R₃ is methylthio. Insome embodiments, R₃ is N-morpholino. In some embodiments, R₃ is H.

In some embodiments of Formula (I) or Formula (II), R₄ is selected fromH, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl is optionally substituted with a substituent selected from S(C₁₋₄alkyl), NR^(c2)R^(d2), and NR^(c2)C(═NR^(c2))NR^(c2)R^(d2). In someembodiments, R₄ is selected from C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with asubstituent selected from S(C₁₋₄ alkyl), NR^(c2)R^(d2), andNR^(c2)C(═NR^(e2))NR^(c2)R^(d2). In some embodiments, R₄ is C₁₋₆ alkyl.In some embodiments, R₄ is C₁₋₆ hydroxyalkyl. In some embodiments, R₄ isC₂₋₆ alkenyl. In some embodiments, R₄ is C₁₋₆ alkyl substituted withS(C₁₋₄ alkyl). In some embodiments, R₄ is C₁₋₆ alkyl is substituted withNR^(c2)R^(d2). In some embodiments, R₄ is C₁₋₆ alkyl substituted withNR^(c2)C(═NR^(e2))NR^(c2)R^(d2). In some embodiments, R₄ is C₁₋₃ alkylsubstituted with NH(pyridin-2-yl). In some embodiments, R₄ is C₁₋₃ alkylsubstituted with NH(imidazol-2-yl). In some embodiments, R₄ is selectedfrom H, methyl, methylthiomethyl, hydroxymethyl, CH₂NH(imidazol-2-yl),guanidinomethyl, ethenyl, CH₂NH(pyridin-2-yl), and aminomethyl. In someembodiments, R₄ is selected from methyl, methylthiomethyl,hydroxymethyl, CH₂NH(imizadol-2-yl), guanidinomethyl, ethenyl,CH₂NH(pyridin-2-yl), and aminomethyl. In some embodiments, R₄ is methyl.In some embodiments, R₄ is methylthiomethyl. In some embodiments, R₄ ishydroxymethyl. In some embodiments, R₄ is CH₂NH(imizadol-2-yl). In someembodiments, R₄ is CH₂NH(pyridin-2-yl). In some embodiments, R₄ isguanidinomethyl. In some embodiments, R₄ is ethenyl. In someembodiments, R₄ is aminomethyl. In some embodiments, R₄ is H.

In some embodiments of Formula (I) or Formula (II), thestereoconfiguration of the carbon atom to which R₄ is attached is (S)according to Cahn-Ingold-Prelog nomenclature. In some embodiments, thestereoconfiguration of the carbon atom to which R₄ is attached is (R)according to Cahn-Ingold-Prelog nomenclature.

In some embodiments, the stereochemistry at the carbon atom bound to R₄is as shown below:

wherein x indicates a point of attachment to the X atom.

In some embodiments, the stereochemistry at the carbon atom bound to R₄is as shown below:

wherein x indicates a point of attachment to the X atom.

In some embodiments of Formula (I) or Formula (II), X is NR₅. In someembodiments, X is NH. In some embodiments, X is O. In some embodiments,X is CH₂. In some embodiments of Formula (I) or Formula (II), R₅ is H.

In some embodiments of Formula (I) or Formula (II), W is CR^(6A)R^(6B).In some embodiments, W is NR^(6A).

In some embodiments of Formula (I) or Formula (II), when X is O, then Wis not NR^(6A). In some embodiments, when X is NR₅, then W is notNR^(6A). In some embodiments, W is CR^(6A)R^(6B), R^(6B) is H and R^(6A)is selected from H, methyl, trifluoromethyl, and difluoromethyl. In someembodiments, R^(6A) is selected from H, methyl, trifluoromethyl, anddifluoromethyl.

In some embodiments of Formula (I) or Formula (II), thestereoconfiguration of the carbon atom to which R_(6A) is attached is(S) according to Cahn-Ingold-Prelog nomenclature. In some embodiments,the stereoconfiguration of the carbon atom to which R_(6A) is attachedis (R) according to Cahn-Ingold-Prelog nomenclature.

In some embodiments, the stereochemistry at the carbon atom bound toR_(6A) is as shown below:

wherein x indicates a point of attachment to the X atom.

In some embodiments, the stereochemistry at the carbon atom bound toR_(6A) is as shown below:

wherein x indicates a point of attachment to the X atom.

In some embodiments of Formula (I) or Formula (II), W is CR^(6A)R^(6B),R^(6B) is H and R^(6A) is selected from H, methyl, trifluoromethyl, anddifluoromethyl. In some embodiments, W is CR^(6A)R^(6B), R^(6B) is H andR^(6A) is H. In some embodiments, W is CR^(6A)R^(6B), Rl^(6B) is H andR^(6A) is methyl. In some embodiments, W is CR^(6A)R^(6B), R^(6B) is Hand R^(6A) is trifluoromethyl. In some embodiments, W is CR^(6A)R^(6B),R^(6B) is H and R^(6A) difluoromethyl. In some embodiments, R^(6A) andR^(6B) together form an oxo group. In some embodiments of Formula (I) orFormula (II), R₄ is methylthiomethyl and R^(6A) is H.

In some embodiments of Formula (I) or Formula (II), W is CR^(6A)R^(6B),R^(6A) is H, R^(6B) is H, and R₄ is methylthiomethyl. In someembodiments, W is CR^(6A)R^(6B), R^(6A) is H, R^(6B) is H, and R₄ ismethyl. In some embodiments, W is CR^(6A)R^(6B), R^(6A) and R^(6B)together form an oxo group and R₄ is selected from C₁₋₆ alkyl, C₁₋₆hydroxyalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionallysubstituted with a substituent selected from NR^(c2)R^(d2) andNR^(c2)C(═NR^(e2))NR^(c2)R^(d2). In some embodiments, W isCR^(6A)R^(6B), R^(6A) and R^(6B) together form an oxo group and R₄ isC₁₋₆ alkyl. In some embodiments, W is CR^(6A)R_(6B), R_(6A) and R_(6B)together form an oxo group and R₄ is C₁₋₆ hydroxyalkyl. In someembodiments, W is CR^(6A)R^(6B), R^(6A) and R^(6B) together form an oxogroup and R₄ is C₂₋₆ alkenyl. In some embodiments, W is CR^(6A)R^(6B),R^(6A) and R^(6B) together form an oxo group and R₄ is C₁₋₆ alkylsubstituted with NR^(c2)R^(d2) or NR^(c2)C(═NR^(e2))NR^(c2)R^(d2). Insome embodiments, W is CR^(6A)R^(6B), R^(6A) and R^(6B) together form anoxo group and R₄ is selected from methyl, methylthiomethyl,hydroxymethyl, CH₂NH(imizadol-2-yl), CH₂NH(pyridin-2-yl),guanidinomethyl, ethenyl, and aminomethyl. In some embodiments, W isCR^(6A)R^(6B), R_(6A) and R_(6B) together form an oxo group and R₄ ismethyl. In some embodiments of Formula (I) or Formula (II), W isCR^(6A)R^(6B), R^(6A) and R_(6B) together form an oxo group and R₄ ismethylthiomethyl. In some embodiments, W is CR^(6A)R^(6B), R^(6A) andR^(6B) together form an oxo group and R₄ is hydroxymethyl. In someembodiments, W is CR^(6A)R^(6B), R^(6A) and R^(6B) together form an oxogroup and R₄ is CH₂NH(imizadol-2-yl) or CH₂NH(pyridin-2-yl). In someembodiments, W is CR_(6A)R_(6B), R_(6A) and R_(6B) together form an oxogroup and R₄ is guanidinomethyl. In some embodiments, W isCR^(6A)R^(6B), R^(6A) and R^(6B) together form an oxo group and R₄ isethenyl. In some embodiments, W is CR^(6A)R^(6B), R^(6A) and R^(6B)together form an oxo group and R₄ is aminomethyl.

In some embodiments of Formula (I) or Formula (II), R^(6A) and R₄together with the carbon atom to which R₄ is attached, the W atom towhich R^(6A) is attached and the X atom connecting W and the carbon atomto which R₄ is attached, form a ring of any one of the followingformulae:

-   wherein x indicates a point of attachment to the ring containing Y,

In some embodiments of Formula (I) or Formula (II), R^(6A) and R₄together with the carbon atom to which R₄ is attached, the W atom towhich R^(6A) is attached and the X atom connecting W and the carbon atomto which R₄ is attached, form a ring of formula:

In some embodiments of Formula (I) or Formula (II), R^(6A) and R₄together with the carbon atom to which R₄ is attached, the W atom towhich R^(6A) is attached and the X atom connecting W and the carbon atomto which R₄ is attached, form a ring of formula:

In some embodiments of Formula (I) or Formula (II), R^(6A) and R₄together with the carbon atom to which R₄ is attached, the W atom towhich R^(6A) is attached and the X atom connecting W and the carbon atomto which R₄ is attached, form a ring of formula:

In some embodiments of Formula (I) or Formula (II), R^(6A) and R₄together with the carbon atom to which R₄ is attached, the W atom towhich R^(6A) is attached and the X atom connecting W and the carbon atomto which R₄ is attached, form a ring of formula:

-   wherein x indicates a point of attachment to the ring containing Y.

In some embodiments of Formula (I) or Formula (II), R^(6A) and R₄together with the carbon atom to which R₄ is attached, the W atom towhich R^(6A) is attached and the X atom connecting W and the carbon atomto which R₄ is attached, form a ring of formula:

In some embodiments of Formula (I) or Formula (II), R^(6A) and R₄together with the carbon atom to which R₄ is attached, the W atom towhich R^(6A) is attached and the

X atom connecting W and the carbon atom to which R₄ is attached, form aring of formula:

-   wherein x indicates a point of attachment to the ring containing Y.

In some embodiments of Formula (I) or Formula (II), R^(6A) and R₄together with the carbon atom to which R₄ is attached, the W atom towhich R^(6A) is attached and the X atom connecting W and the carbon atomto which R₄ is attached, form a ring of any one of the followingformulae:

wherein x indicates a point of attachment to the ring containing Y.

In some embodiments of Formula (I) or Formula (II), R^(6A) and R₄together with the carbon atom to which R₄ is attached, the W atom towhich R^(6A) is attached and the X atom connecting W and the carbon atomto which R₄ is attached, form a ring of any one of the followingformulae:

-   wherein x indicates a point of attachment to the ring containing Y.

In some embodiments of Formula (I) or Formula (II), R₇ is selected frommethyl, trifluoromethyl, and cyclopropyl. In some embodiments, R₇ ismethyl.

In some embodiments of Formula (I) or Formula (II), the carbon atom towhich R₇ is attached is in (S) configuration. As used herein, theconfiguration at the stereocenter is determined according toCahn-Ingold-Prelog nomenclature. In some embodiments, thestereochemistry at the carbon atom bound to R₇ is as shown below:

In some embodiments of Formula (I) or Formula (II), each R^(a1), R^(b1),R^(c1), R^(d1), R^(a2), R^(c2), and R^(d2) is selected from H, C₁₋₄alkyl, and C₁₋₄ haloalkyl. In some embodiments, R^(a1) is H. In someembodiments, R^(a1) is C₁₋₄ alkyl. In some embodiments, R^(a1) is C₁₋₄haloalkyl. In some embodiments, R^(b1) is C₁₋₄ alkyl. In someembodiments, R^(c1) is H, and R^(d2) is selected from H, C₁₋₄ alkyl,C₁₋₄ haloalkyl, and 5- to 6-membered heteroaryl. In some embodiments,R^(c1) is H, and R^(d2) is C₁₋₄ alkyl. In some embodiments, R^(c1) is H,and R^(d2) is 5- to 6-membered heteroaryl. In some embodiments, R^(c1)is H, and R^(d2) is pyridin-2-yl. In some embodiments, R^(c1) is H, andR^(d2) is imidazol-2-yl. In some embodiments of Formula (I) or Formula(II), R₈ is selected from H, C₁₋₄ alkenyl, C₁₋₄ haloalkyl, C₃₋₅cycloalkyl and C₁₋₄ alkyl optionally substituted with a substituentselected from amino, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-memberedheterocycloalkyl. In some embodiments, R₈ is selected from H, allyl,fluoromethyl, cyclopropyl, methoxymethyl, aminomethyl,(N-azetidinyl)methyl, oxetanyl-methyl, cyclopropyl-methyl, vinyl, propyland isopropyl. In some embodiments, R₈ is H. In some embodiments, R₈ isC₁₋₆ alkyl. In some embodiments, R₈ is selected from H, methyl, ethyl,n-propyl and i-propyl. In some embodiments, R₈ is methyl. In someembodiments, R₈ is ethyl. In some embodiments, R₈ is n-propyl. In someembodiments, R₈ is i-propyl. In some embodiments, R₈ is cyclopropyl. Insome embodiments, R₈ is vinyl. In some embodiments, R₈ is allyl. In someembodiments, R₈ is fluoromethyl. In some embodiments, R₈ ismethoxymethyl. In some embodiments, R₈ is aminomethyl. In someembodiments of Formula (I) or Formula (II), the carbon atom to which R₈is attached is in (S) configuration according to Cahn-Ingold-Prelognomenclature. In some embodiments, the carbon atom to which R₈ isattached is in (R) configuration according to Cahn-Ingold-Prelognomenclature. In some embodiments, the stereochemistry at the carbonatom bound to R₈ is as shown below:

In some embodiments, the stereochemistry at the carbon atom bound to R₈is as shown below:

In some embodiments of Formula (I) or Formula (II), R^(e2) is H.

In some embodiments of Formula (I), R₉ is selected from H and halo. Insome embodiments, R₉ is H. In some embodiments, R₉ is halo. For example,R₉ can be fluoro.

In Some Embodiments of Formula (I):

R_(i) is fluoro;

R₂ is chloro;

Y is CR₃;

R₃ is selected from H, halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1),SR^(a1), S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromC(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄alkoxy is optionally substituted with C₁₋₄ alkoxy;

R₄ is selected from H, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from S(C₁₋₄ alkyl), NR^(c2)R^(d2) andNR^(c2)C(═NR^(e2))NR^(c2)R^(d2);

X is NR₅;

W is CR^(6A)R^(6B);

R^(6A) is selected from H, methyl, trifluoromethyl, and difluoromethyl;

R₇ is selected from methyl, trifluoromethyl, and cyclopropyl;

R₈ is selected from H, methyl, ethyl, n-propyl and i-propyl; and

R₉ is selected from H and halo.

In Some Embodiments of Formula (I):

R₁ is fluoro;

R₂ is chloro;

Y is CR₃;

R₃ is selected from H, halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1),SR^(a1), S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromC(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄alkoxy is optionally substituted with C₁₋₄ alkoxy;

R₄ is selected from H, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from S(C₁₋₄ alkyl), NR^(c2)R^(d2) andNR^(c2)C(═NR^(e2))NR^(c2)R^(d2);

X is NR₅;

W is CR^(6A)R^(6B);

R^(6A) is selected from H, methyl, trifluoromethyl, and difluoromethyl;

R₇ is selected from methyl, trifluoromethyl, and cyclopropyl;

R₈ is selected from H, methyl, ethyl, n-propyl and i-propyl; and

R₉ is H.

In Some Embodiments of Formula (I):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is selected from H, fluoro, NO₂, methylsulfonyl, methoxy, methylthio,carboxymethyl, methylaminocarbonylmethyl, N-morpholino,(2-methoxyethoxy)methyl, and dimethylamino;

R₄ is selected from H, methyl, methylthiomethyl, hydroxymethyl,CH₂NH(imidazol-2-yl), guanidinomethyl, ethenyl, CH₂NH(pyridin-2-yl), andaminomethyl;

X is NH;

W is CR^(6A)R^(6B);

R^(6A) is selected from H, methyl, trifluoromethyl, and difluoromethyl;

R₇ is selected from methyl, trifluoromethyl, and cyclopropyl;

R₈ is selected from H, methyl, ethyl, n-propyl and i-propyl; and

R₉ is H.

In some embodiments of Formula (I):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;R₃ is selected from NR^(c1)R^(d1), NO₂, S(O)₂R^(b1), and 5- to6-membered heterocycloalkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with a substituent selected from C(O)OR^(a1),C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄ alkoxy isoptionally substituted with C₁₋₄ alkoxy;

R₄ is C₁₋₆ alkyl;

X is NH;

W is CH₂;

R₇ is methyl;

R₈ is H; and

R₉ is H.

In Some Embodiments of Formula (I):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is selected from dimethylamine, NO₂, methylsulfonyl, andN-morpholino, carboxymethyl, methylaminocarbonylmethyl, and(2-methoxyethoxy)methyl;

R₄ is methyl;

X is NH;

W is CH₂;

R₇ is methyl;

R₈ is H; and

R₉ is H.

In Some Embodiments of Formula (I):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is H;

R₄ is selected from C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from NR^(c2)R^(d2) and NR^(c2)C(═NR^(e2))NR^(c2)R^(d2);

X is NH;

W is CR^(6A)R^(6B);

R^(6A) and R^(6B) together form an oxo group;

R₇ is methyl;

R₈ is H; and

R₉ is H.

In Ssome Embodiments of Formula (I):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is H;

X is NH;

R₄ is selected from methyl, methylthiomethyl, hydroxymethyl,CH₂NH(imizado1-2-yl), CH₂NH(pyridin-2-yl), guanidinomethyl, ethenyl, andaminomethyl

W is CR^(6A)R^(6B);

R^(6A) and R^(6B) together form an oxo group;

R₇ is methyl;

R₈ is H; and

R₉ is H.

In Some Embodiments of Formula (I):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is selected from halo, OR^(a1), and SR^(a1);

X is O;

R₄ is C₁₋₆ alkyl substituted with NR^(c2)C(═NR^(e2))NR^(c2)R^(d2);

W is CH₂;

R₇ is methyl;

R₈ is H; and

R₉ is H.

In Some Embodiments of Formula (I):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is selected from fluoro, methoxy, and methylthio;

X is O; R₄ is guanidinomethyl;

W is CH₂;

R₇ is methyl;

R₈ is H; and

R₉ is H.

In Some Embodiments of Formula (I):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is selected from halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1),SR^(a1), S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromC(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄alkoxy is optionally substituted with C₁₋₄ alkoxy;

R^(6A) and R₄ together with the carbon atom to which R₄ is attached, theW atom to which R^(6A) is attached and the X atom connecting W and thecarbon atom to which R₄ is attached, form a ring of any one of thefollowing formulae:

wherein x indicates a point of attachment to the phenyl ring substitutedwith R₃;

R₇ is selected from C₁₋₄ alkyl and C₃₋₅ cycloalkyl;

R₈ is H; and

R₉ is H.

In Some Embodiments of Formula (I):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is H;

W is CR^(6A)R^(6B) or NR^(6A);

R^(6A) and R₄ together with the carbon atom to which R₄ is attached, theW atom to which R^(6A) is attached and the X atom connecting W and thecarbon atom to which R₄ is attached, form a ring of any one of thefollowing formulae:

wherein x indicates a point of attachment to the phenyl ring substitutedwith R₃;

R₇ is selected from methyl or cyclopropyl;

R₈ is H; and

R₉ is H.

In Some Embodiments of Formula (II):

R₁ is fluoro;

R₂ is chloro;

Y is CR₃;

R₃ is selected from H, halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1),SR^(a1), S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromC(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄alkoxy is optionally substituted with C₁₋₄ alkoxy;

R₄ is selected from H, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from S(C₁₋₄ alkyl), NR^(c2)R^(d2) andNR^(c2)C(═NR^(e2))NR^(c2)R^(d2);

X is NR₅;

W is CR^(6A)R^(6B);

R^(6A) is selected from H, methyl, trifluoromethyl, and difluoromethyl;

R₇ is selected from methyl, trifluoromethyl, and cyclopropyl; and

R₈ is selected from H, methyl, ethyl, n-propyl and i-propyl.

In Some Embodiments of Formula (II):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is selected from H, fluoro, NO₂, methylsulfonyl, methoxy, methylthio,carboxymethyl, methylaminocarbonylmethyl, N-morpholino,(2-methoxyethoxy)methyl, and dimethylamino;

R₄ is selected from H, methyl, methylthiomethyl, hydroxymethyl,CH₂NH(imidazol-2-yl), guanidinomethyl, ethenyl, CH₂NH(pyridin-2-yl), andaminomethyl;

X is NH;

W is CR^(6A)R^(6B);

R^(6A) is selected from H, methyl, trifluoromethyl, and difluoromethyl;

R₇ is selected from methyl, trifluoromethyl, and cyclopropyl; and

R₈ is selected from H, methyl, ethyl, n-propyl and i-propyl.

In Some Embodiments of Formula (II):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;R₃ is selected from NR^(c1)R^(d1), NO₂, S(O)₂R^(b1), and 5- to6-membered heterocycloalkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with a substituent selected from C(O)OR^(a1),C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄ alkoxy isoptionally substituted with C₁₋₄ alkoxy;

R₄ is C₁₋₆ alkyl;

X is NH;

W is CH₂;

R₇ is methyl; and

R₈ is H.

In Some Embodiments of Formula (II):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is selected from dimethylamine, NO₂, methylsulfonyl, andN-morpholino, carboxymethyl, methylaminocarbonylmethyl, and(2-methoxyethoxy)methyl;

R₄ is methyl;

X is NH;

W is CH₂;

R₇ is methyl; and

R₈ is H.

In Some Embodiments of Formula (II):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is H;

R₄ is selected from C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from NR^(c2)R^(d2) and NR^(c2)(═NR^(e2))NR^(c2)R^(d2);

X is NH;

W is CR^(6A)R^(6B);

R^(6A) and R^(6B) together form an oxo group;

R₇ is methyl; and

R₈ is H.

In Some Embodiments of Formula (II):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is H;

X is NH;

R₄ is selected from methyl, methylthiomethyl, hydroxymethyl,CH₂NH(imizadol-2-yl), CH₂NH(pyridin-2-yl), guanidinomethyl, ethenyl, andaminomethyl

W is CR^(6A)R^(6B);

R^(6A) and R^(6B) together form an oxo group;

R₇ is methyl; and

R₈ is H.

In Some Embodiments of Formula (II):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is selected from halo, OR^(a1), and SR^(a1);

X is O;

R₄ is C₁₋₆ alkyl substituted with NR^(c2)C(═NR^(e2))NR^(c2)R^(d2);

W is CH₂;

R₇ is methyl; and

R₈ is H.

In Some Embodiments of Formula (II):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is selected from fluoro, methoxy, and methylthio;

X is O;

R₄ is guanidinomethyl;

W is CH₂;

R₇ is methyl; and

R₈ is H.

In Some Embodiments of Formula (II):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is selected from halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1),SR^(a1), S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromC(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄alkoxy is optionally substituted with C₁₋₄ alkoxy;

R^(6A) and R₄ together with the carbon atom to which R₄ is attached, theW atom to which R^(6A) is attached and the X atom connecting W and thecarbon atom to which R₄ is attached, form a ring of any one of thefollowing formulae:

wherein x indicates a point of attachment to the phenyl ring substitutedwith R₃;

R₇ is selected from C₁₋₄ alkyl and C₃₋₅ cycloalkyl and

R₈ is H.

In Some Embodiments of Formula (II):

R₁ is fluoro;

R₂ is chloro;

Y is CR³;

R₃ is H;

W is CR^(6A)R^(6B) or NR^(6A);

R^(6A) and R₄ together with the carbon atom to which R₄ is attached, theW atom to which R^(6A) is attached and the X atom connecting W and thecarbon atom to which R₄ is attached, form a ring of any one of thefollowing formulae:

wherein x indicates a point of attachment to the phenyl ring substitutedwith R₃;

R₇ is selected from methyl or cyclopropyl; and

R₈ is H.

In some embodiments, the compounds of Formula (I) or Formula (II) haveFormula (A-I):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein Y, R₁, R₂, R₃, R₄, R^(6A), R₇, and R₈ areas described herein.

In some embodiments, the compounds of Formula (I) or Formula (II) haveFormula (Ia) or Formula (Ib):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer;

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer,

wherein R₁, R₂, R₃, R₄, R^(6A), and R₇ are as described herein.

In some embodiments, the compounds of Formula (I) or Formula (II) haveFormula (Ic):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer.

In some embodiments, the compounds of Formula (I) or Formula (II) haveFormula (Ic-1):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer.

In some embodiments, the compounds of Formula (I) or Formula (II) haveFormula (Id):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer.

In some embodiments, the compounds of Formula (I) or Formula (II) haveany one of Formulae (Ie)-(Ii):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer; and

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer;

In some embodiments of any one of the Formulae disclosed herein, thefragment

In some embodiments of any one of the Formulae disclosed herein, thefragment

-   is selected from

In some embodiments of any one of the Formulae disclosed herein, thefragment

-   is selected from any one of the following fragments:

In some embodiments of any one of the Formulae disclosed herein, thefragment

In some embodiments of any one of the Formulae disclosed herein, thefragment

-   is selected from any one of the following fragments:

In some embodiments, the compounds of any one of Formulae disclosedherein are not any one of the compounds of Table 3 below:

TABLE 3

or a tautomer or a pharmaceutically acceptable salt of the compound ortautomer.

In some embodiments, the compounds of Formula (I) or Formula (II) arenot any of the exemplified compounds disclosed in PCT application No.PCT/US2010/052922 (published as WO 2011/047319), PCT application No.PCT/US2012/032994 (published as WO 2012/173689), PCT application No.PCT/US2014/054869 (published as WO 2015/035426), PCT application No.PCT/US2014/054860 (published as WO 2015/035421); or PCT application No.PCT/US2016/022216.

In some embodiments, the compounds of Formula (I) or Formula (II) arenot any of the compounds 194, 234, 119, 379, 269, 268, 392, 415, 433,374, 341, 462, 463 and 105 disclosed in PCT application No.PCT/US2012/032994 (published as WO 2012/173689).

In some embodiments, the compounds of Formula (I) or Formula (II) arenot any of the compounds 433, 420, 438, 444, 349, 285, 527, 353, 384,405, 469, 407, 526, 555, 219, 225, 246, 317, 370, 209, 195, 150, 74, 95,168, 135, 382, 387, 249, 273, 291, 303, 367, 340, 355, 379, 536, 491,524, 534, and 459 disclosed in PCT application No. PCT/US2014/054869(published as WO 2015/035426).

In some embodiments, the compounds of Formula (I) or Formula (II) arenot any of the compounds 4, 13, 21, 48, 54, 58, 30, 31, 32, 33, 38, 49,57, 59, 71, 60, 64, 66, 68, 73, 74, 75, 76, 87, 88, 92, 119, 132, 133,134, 159, 162, 164, and 174 disclosed in PCT application No.PCT/US2016/022216.

In some embodiments, a compound of Formula (I) or Formula (II) is anyone of the compounds listed in Table 1, or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer.

TABLE 1 ESI, m/z # Structure [M + H]⁺ 1

625 2

638 5

595.7 6

645 7

594.6 8

612 9

10

597 11

610 12

655 14

595.6 15

662 16

652 17

594.5 18

594.5 19

638 20

593 21

673 22

594.4 23

594.5 24

613 25

596 26

621.4 27

621.4 28

603.5 29

637.4 30

643.3 31

671.5 32

655.4

In some embodiments, the present disclosure provides any one ofcompounds listed in Table 1a, or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer.

TABLE 1a # Structure 33

34

35

36

37

39

44

45

46

47

48

49

50

51

52

53

54

55

In some embodiments, the present disclosure provides any one ofcompounds listed in Table 1b, or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer.

TABLE 1b ESI, m/z # Structure [M + H]⁺ 56

661

In some embodiments, the present disclosure relates to a compound or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer that binds the ribosome. In some embodiments, the ribosomeis a bacterial ribosome.

In some embodiments, the present disclosure relates to a pharmaceuticalcomposition comprising a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer, and a pharmaceutically acceptable carrier. In someembodiments, the present disclosure relates to a compound or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer disclosed herein and a means for delivery.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of or delaying the onset of adisease state in a human or animal comprising administering to the humanor animal in need thereof an effective amount of a compound disclosedherein, or a tautomer thereof, or a pharmaceutically acceptable salt ofsaid compound or tautomer.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer.

In some embodiments, the present disclosure relates to use of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of, a microbial infection in a human or animal. In anotheraspect, the present disclosure relates to a compound for use in themanufacture of a medicament for treating a microbial infection in asubject, wherein the compound is selected from a compound of the presentdisclosure, or a tautomer thereof, or a pharmaceutically acceptable saltof said compound or tautomer.

In some embodiments, the present disclosure relates to a compound foruse in the manufacture of a medicament for preventing a microbialinfection in a subject, wherein the compound is selected from a compoundof the present disclosure, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer.

In some embodiments, the present disclosure relates to a compound foruse in the manufacture of a medicament for reducing the risk of amicrobial infection in a subject, wherein the compound is selected froma compound of the present disclosure, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer.

In some embodiments, the present disclosure relates to a compound foruse in the manufacture of a medicament for delaying the onset of amicrobial infection in a subject, wherein the compound is selected froma compound of the present disclosure, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, for use in treating,preventing, reducing the risk of, or delaying the onset of a microbialinfection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, for use in treating amicrobial infection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, for use in preventing amicrobial infection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, for use in reducing therisk of a microbial infection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, for use in delaying theonset of a microbial infection in a human or animal.

In some embodiments, a microbial infection as described herein is causedby one or more microoganisms selected from the group consisting of:Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae,Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species,and Escherichia coli. This group of microoganisms can be referred togenerally as the ESKAPE pathogens. In some embodiments, the microbialinfection is caused by a microorganism which is resistant to at leastone antibacterial. For example, the microorganism can be classified asmulti-drug resistant or extremely-drug resistant.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer,wherein said microbial infection is caused by one or more of thefollowing microorganisms: Acinetobacter spp. (Acinetobacter baumanni),Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovatus,Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroidesvulgatus, Citrobacter freundii, Citrobacter koser, Chlamydiatrachomatis, Chlamydia psittaci, Chlamydia pneumoniae, Chlamydiapecorum, hlamydia suis, Chlaymdia muridarum, Chlamydophila psittaci,Chlamydophila pneumoniae, Chlamydophila pecorum, Clostridiumclostridioforme, Clostridium perfringens, Enterobacter aerogenes,Enterobacter cloacae, Enterococcus faecalis, Enterococcus spp.(vancomycin susceptible and resistant isolates), Escherichia coli(including ESBL and KPC producing isolates), Eubacterium lentum,Fusobacterium spp., Haemophilus influenzae (including beta-lactamasepositive isolates), Haemophilus parainfluenzae, Klebsiella pneumoniae(including ESBL and KPC producing isolates), Klebsiella oxytoca(including ESBL and KPC producing isolates), Legionella pneumophiliaMoraxella catarrhalis, Morganella morganii, Mycoplasma spp., Neisseriagonorrhoeae (including Neisseria gonorrhoeae ATCC_(49266,) Neisseriagonorrhoeae 255123, Neisseria gonorrhoeae 255124, Neisseria gonorrhoeae255125, Neisseria gonorrhoeae 255126, Neisseria gonorrhoeae 255127,Neisseria gonorrhoeae J9104300210, Neisseria gonorrhoeae J9107400107,Neisseria gonorrhoeae J9109510210, Neisseria gonorrhoeae J9108110210),Peptostreptococcus spp., Porphyromonas asaccharolytica, Prevotellabivia, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri,Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens,Streptococcus anginosus, Staphylococcus aureus (methicillin susceptibleand resistant isolates), Staphylococcus epidermidis (methicillinsusceptible and resistant isolates), Stenotrophomonas maltophilia,Streptococcus agalactiae, Streptococcus constellatus, Streptococcuspneumoniae (penicillin susceptible and resistant isolates),Streptococcus pyogenes, or Streptococcus pyogenes.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer,wherein said infection is caused by or involves one or moremicroorganisms selected from: Acinetobacter spp. (Acinetobacterbaumanni), Bacteroides distasonis, Bacteroides fragilis, Bacteroidesovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroidesvulgatus, Citrobacter freundii, Citrobacter koser, Chlamydiatrachomatis, Chlamydia psittaci, Chlamydia pneumoniae, Chlamydiapecorum, hlamydia suis, Chlaymdia muridarum, Chlamydophila psittaci,Chlamydophila pneumoniae, Chlamydophila pecorum, Clostridiumclostridioforme, Clostridium perfringens, Enterobacter aerogenes,Enterobacter cloacae, Enterococcus faecalis, Enterococcus spp.,Escherichia coli, Eubacterium lentum, Fusobacterium spp., Haemophilusinfluenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae,Klebsiella oxytoca, Legionella pneumophilia, Moraxella catarrhalis,Morganella morganii, Mycoplasma spp., Neisseria gonorrhoeae,Peptostreptococcus spp., Porphyromonas asaccharolytica, Prevotellabivia, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri,Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens,Streptococcus anginosus, Staphylococcus aureus, Staphylococcusepidermidis, Stenotrophomonas maltophilia, Streptococcus agalactiae,Streptococcus constellatus, Streptococcus pneumoniae, Streptococcuspyogenes, and Streptococcus pyogenes.

In some embodiments, the present disclosure relates to a method whereinsaid infection is caused by or involves one or more of aerobic andfacultative gram-positive microorganisms selected from: Staphylococcusaureus, Streptococcus pneumoniae, Enterococcus spp., Streptococcusagalactiae, Streptococcus pyogenes, and Staphylococcus epidermidis.

In some embodiments, the present disclosure relates to a method whereinsaid infection is caused by or involves one or more of aerobic andfacultative gram-negative microorganisms selected from: Escherichiacoli, Haemophilus influenzae, Klebsiella pneumoniae, Citrobacterfreundii, Chlamydia trachomatis, Chlamydia psittaci, Chlamydiapneumoniae, Chlamydia pecorum, hlamydia suis, Chlaymdia muridarum,Chlamydophila psittaci, Chlamydophila pneumoniae, Chlamydophila pecorum,Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii,Neisseria gonorrhoeae, Serratia marcescens, Pseudomonas aeruginosa,Acinetobacter baumanni, Moraxella catarrhalis, Proteus mirabilis,Citrobacter koseri, Haemophilus parainfluenzae, Klebsiella oxytoca,Proteus vulgaris, Providencia rettgeri, and Providencia stuartii.

In some embodiments, the present disclosure relates to a method wherein,said infection is caused by or involves one or more anaerobicmicroorganisms: Bacteroides fragilis, Bacteroides distasonis,Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis,Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcusspp., Porphyromonas asaccharolytica, Prevotella bivia, Bacteroidesvulgatus, Clostridium perfringens, and Fusobacterium spp.

In some embodiments, the present disclosure relates to a method, whereinthe microorganism Enterococcus spp. is selected from vancomycinsusceptible isolate and vancomycin resistant isolate.

In some embodiments, the present disclosure relates to a method wherein,the microorganism Escherichia coli is selected from extended spectrumbeta-lactamase (ESBL) producing isolate and Klebsiella pneumoniaecarbapenemase (KPC) producing isolate.

In some embodiments, the present disclosure relates to a method wherein,the microorganism Haemophilus influenzae is a beta-lactamase positiveisolate.

In some embodiments, the present disclosure relates to a method wherein,the microorganism Klebsiella pneumoniae is selected from extendedspectrum beta-lactamase (ESBL) producing isolate and Klebsiellapneumoniae carbapenemase (KPC) producing isolate.

In some embodiments, the present disclosure relates to a method wherein,the microorganism Klebsiella oxytoca selected from extended spectrumbeta-lactamase (ESBL) producing isolate and Klebsiella pneumoniaecarbapenemase (KPC) producing isolate.

In some embodiments, the present disclosure relates to a method wherein,the microorganism Staphylococcus aureus is selected from methicillinsusceptible isolate and methicillin resistant isolate.

In some embodiments, the present disclosure relates to a method wherein,the microorganism Staphylococcus epidermidis is selected frommethicillin susceptible isolate and methicillin resistant isolate.

In some embodiments, the present disclosure relates to a method wherein,the microorganism Streptococcus pneumoniae is selected from penicillinsusceptible isolate and penicillin resistant isolate.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer,wherein said microbial infection is caused by or involves one or moremicroorganisms which are capable of being used as biological weapons,e.g., wherein the one or more microorganisms are selected from Bacillusanthracis and Multi Drug Resistant (MDR) anthracis, Franciscellatularensis, Yersinia pestis, Burkholderia mallei, and Burkholderiapseudomallei.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer,wherein said microbial infection is caused by one or more of thefollowing microorganisms: Bacillus anthracis and Multi Drug Resistant(MDR) anthracis, Franciscella tularensis, Yersinia pestis, Burkholderiamallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, or a pharmaceutical composition thereof, or use of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or a pharmaceuticalcomposition thereof, in the manufacture of a medicament for treating,preventing, reducing the risk of, or delaying the onset of a microbialinfection in a human or animal, wherein the microbial infection iscaused by or involves one or more microorganisms which are capable ofbeing used as biological weapons, e.g., wherein the one or moremicroorganisms are selected from Bacillus anthracis and Multi DrugResistant (MDR) anthracis, Franciscella tularensis, Yersinia pestis,Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, or a pharmaceutical composition thereof, wherein themicrobial infection is caused by or involves one or more microorganismswhich are capable of being used as biological weapons, e.g., wherein theone or more microorganisms are selected from Bacillus anthracis andMulti Drug Resistant (MDR) anthracis, Franciscella tularensis, Yersiniapestis, Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to a method oftreating a microbial infection in a human or animal comprisingadministering to the human or animal an effective amount of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or a pharmaceuticalcomposition thereof, wherein the microbial infection is caused by orinvolves one or more microorganisms which are capable of being used asbiological weapons, e.g., wherein the one or more microorganisms areselected from Bacillus anthracis and Multi Drug Resistant (MDR)anthracis, Franciscella tularensis, Yersinia pestis, Burkholderiamallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to a method ofpreventing a microbial infection in a human or animal comprisingadministering to the human or animal an effective amount of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or a pharmaceuticalcomposition thereof, wherein the microbial infection is caused by orinvolves one or more microorganisms which are capable of being used asbiological weapons, e.g., wherein the one or more microorganisms areselected from Bacillus anthracis and Multi Drug Resistant (MDR)anthracis, Franciscella tularensis, Yersinia pestis, Burkholderiamallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to a method ofreducing the risk of a microbial infection in a human or animalcomprising administering to the human or animal an effective amount of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or a pharmaceuticalcomposition thereof, wherein the microbial infection is caused by orinvolves one or more microorganisms which are capable of being used asbiological weapons, e.g., wherein the one or more microorganisms areselected from Bacillus anthracis and Multi Drug Resistant (MDR)anthracis, Franciscella tularensis, Yersinia pestis, Burkholderiamallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to a method ofdelaying the onset of a microbial infection in a human or animalcomprising administering to the human or animal an effective amount of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or a pharmaceuticalcomposition thereof, wherein the microbial infection is caused by orinvolves one or more microorganisms which are capable of being used asbiological weapons, e.g., wherein the one or more microorganisms areselected from Bacillus anthracis and Multi Drug Resistant (MDR)anthracis, Franciscella tularensis, Yersinia pestis, Burkholderiamallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to the use of one ormore compounds disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, in the manufacture of a medicamentfor treating, preventing, reducing the risk of, or delaying the onset ofa microbial infection in a human or animal, wherein the microbialinfection is caused by or involves one or more microorganisms which arecapable of being used as biological weapons, e.g., wherein the one ormore microorganisms are selected from Bacillus anthracis and Multi DrugResistant (MDR) anthracis, Franciscella tularensis, Yersinia pestis,Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to the use of one ormore compounds disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, in the manufacture of a medicamentfor treating a microbial infection in a human or animal, wherein themicrobial infection is caused by or involves one or more microorganismswhich are capable of being used as biological weapons, e.g., wherein theone or more microorganisms are selected from Bacillus anthracis andMulti Drug Resistant (MDR) anthracis, Franciscella tularensis, Yersiniapestis, Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to the use of one ormore compounds disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, in the manufacture of a medicamentfor preventing a microbial infection in a human or animal, wherein themicrobial infection is caused by or involves one or more microorganismswhich are capable of being used as biological weapons, e.g., wherein theone or more microorganisms are selected from Bacillus anthracis andMulti Drug Resistant (MDR) anthracis, Franciscella tularensis, Yersiniapestis, Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to the use of one ormore compounds disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, in the manufacture of a medicamentfor reducing the risk of a microbial infection in a human or animal,wherein the microbial infection is caused by or involves one or moremicroorganisms which are capable of being used as biological weapons,e.g., wherein the one or more microorganisms are selected from Bacillusanthracis and Multi Drug Resistant (MDR) anthracis, Franciscellatularensis, Yersinia pestis, Burkholderia mallei, and Burkholderiapseudomallei.

In some embodiments, the present disclosure relates to the use of one ormore compounds disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, in the manufacture of a medicamentfor delaying the onset of a microbial infection in a human or animal,wherein the microbial infection is caused by or involves one or moremicroorganisms which are capable of being used as biological weapons,e.g., wherein the one or more microorganisms are selected from Bacillusanthracis and Multi Drug Resistant (MDR) anthracis, Franciscellatularensis, Yersinia pestis, Burkholderia mallei, and Burkholderiapseudomallei.

In some embodiments, the present disclosure pertains, at least in part,to a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, for use in a method of treating,preventing, reducing the risk of, and/or delaying the onset of amicrobial, e.g., bacterial, infection in a subject, wherein theinfection is caused by or involves one or more microorganisms which arecapable of being used as biological weapons, e.g., wherein the one ormore microorganisms are selected from Bacillus anthracis and Multi DrugResistant (MDR) anthracis, Franciscella tularensis, Yersinia pestis,Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure pertains, at least in part,to a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, for use in a method of treating amicrobial, e.g., bacterial, infection in a subject, wherein theinfection is caused by or involves one or more microorganisms which arecapable of being used as biological weapons, e.g., wherein the one ormore microorganisms are selected from Bacillus anthracis and Multi DrugResistant (MDR) anthracis, Franciscella tularensis, Yersinia pestis,Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure pertains, at least in part,to a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, for use in a method of preventing amicrobial, e.g., bacterial, infection in a subject, wherein theinfection is caused by or involves one or more microorganisms which arecapable of being used as biological weapons, e.g., wherein the one ormore microorganisms are selected from Bacillus anthracis and Multi DrugResistant (MDR) anthracis, Franciscella tularensis, Yersinia pestis,Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure pertains, at least in part,to a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, for use in a method of reducing therisk of a microbial, e.g., bacterial, infection in a subject, whereinthe infection is caused by or involves one or more microorganisms whichare capable of being used as biological weapons, e.g., wherein the oneor more microorganisms are selected from Bacillus anthracis and MultiDrug Resistant (MDR) anthracis, Franciscella tularensis, Yersiniapestis, Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure pertains, at least in part,to a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, for use in a method of delaying theonset of a microbial, e.g., bacterial, infection in a subject, whereinthe infection is caused by or involves one or more microorganisms whichare capable of being used as biological weapons, e.g., wherein the oneor more microorganisms are selected from Bacillus anthracis and MultiDrug Resistant (MDR) anthracis, Franciscella tularensis, Yersiniapestis, Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, or use of a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer, in the manufacture of a medicament for treating, preventing,reducing the risk of, or delaying the onset of a microbial infection ina human or animal, wherein the microbial infection is selected from thegroup consisting of: a skin infection, a Gram positive infection, a Gramnegative infection, nosocomial pneumonia, community acquired pneumonia,post-viral pneumonia, hospital acquired pneumonia/ventilator associatedpneumonia, a respiratory tract infection such as chronic respiratorytract infection (CRTI), acute pelvic infection, a complicated skin andskin structure infection, a skin and soft tissue infection (SSTI)including uncomplicated skin and soft tissue infections (uSSTI)s andcomplicated skin and soft tissue infections, an abdominal infection, acomplicated intra-abdominal infection, a urinary tract infection,bacteremia, septicemia, endocarditis, an atrio-ventricular shuntinfection, a vascular access infection, meningitis, surgicalprophylaxis, a peritoneal infection, a bone infection, a jointinfection, a methicillin-resistant Staphylococcus aureus infection, avancomycin-resistant Enterococci infection, a linezolid-resistantorganism infection, gonorrhea, chlamydia, and tuberculosis.

The compounds of the present disclosure can be used, for example for thetreatment of patients with moderate to severe infections, which may becaused by susceptible isolates of the indicated microorganisms.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acomplicated intra-abdominal infection in a human or animal comprisingadministering to the human or animal an effective amount of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or to the use of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of a complicated intra-abdominal infection in a human oranimal.

In some embodiments, the complicated intra-abdominal infection isselected from polymicrobial infections such as abscess due toEscherichia coli, Clostridium clostridioforme, Eubacterium lentum,Peptostreptococcus spp Bacteroides fragilis, Bacteroides distasonis,Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis,Streptococcus anginosus, Streptococcus constellatus, Enterococcusfaecalis, Proteus mirabilis, or Clostridium perfringens.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acomplicated skin and skin structure infection (cSSSI, also known asacute bacterial skin and skin structure infections or ABSSSI) in a humanor animal comprising administering to the human or animal an effectiveamount of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or to theuse of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of a complicated skin and skin structureinfection.

In some embodiments, the complicated skin and skin structure infectionis selected from diabetic foot infections without osteomyelitis due toStaphylococcus aureus (methicillin susceptible and resistant isolates),Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli,Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis,Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotellabivia.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acommunity acquired pneumonia (CAP) in a human or animal comprisingadministering to the human or animal an effective amount of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or to the use of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of community acquired pneumonia.

In some embodiment, the community acquired pneumonia is due toStreptococcus pneumoniae (penicillin susceptible and resistant isolates)including cases with concurrent bacteremia, Haemophilus influenzae(including beta-lactamase positive isolates), Moraxella catarrhalis, oratypical bacteria like Mycoplasma spp.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acomplicated urinary tract infection (cUTI) in a human or animalcomprising administering to the human or animal an effective amount of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or to the use of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of a complicated urinary tract infection.

In some embodiment, the complicated urinary tract infection is selectedfrom pyelonephritis due to Escherichia coli, concurrent bacteremia, orKlebsiella pneumoniae.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of anacute pelvic infection in a human or animal comprising administering tothe human or animal an effective amount of a compound disclosed herein,or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, or to the use of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, in the manufacture of a medicament for treating,preventing, reducing the risk of, or delaying the onset of an acutepelvic infection.

In some embodiments, the acute pelvic infection is selected frompostpartum endomyometritis, septic abortion and post-surgicalgynecologic infections and the infection is due to a microorganismselected from Streptococcus agalactiae, Escherichia coli, Bacteroidesfragilis, Porphyromonas asaccharolytica, Peptostreptococcus spp., andPrevotella bivia.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of ahospital acquired pneumonia (HAP)/ventilator associated pneumonia (VAP)in a human or animal comprising administering to the human or animal aneffective amount of a compound disclosed herein, or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer, orto the use of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of hospital acquired pneumonia/ventilatorassociated pneumonia.

In some embodiments, the hospital acquired pneumonia/ventilatorassociated pneumonia is due to a microorganism selected fromStreptococcus pneumoniae (penicillin susceptible and resistantisolates), Staphylococcus aureus (methicillin susceptible and resistantisolates), Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacterspp., Stenotrophomonas maltophilia, Haemophilus influenzae (includingbeta-lactamase positive isolates), and Legionella pneumophilia.

The compounds or tautomers or pharmaceutically acceptable salts of saidcompounds or tautomers of the present disclosure may also be useful forthe prevention, prophylaxis, or reduction of surgical site infections.In some embodiments, the compounds or tautomers or pharmaceuticallyacceptable salts of said compounds or tautomers of the presentdisclosure are useful following elective colorectal surgery.

Appropriate specimens for bacteriological examination should be obtainedin order to isolate and identify the causative organisms and todetermine their susceptibility to the compounds of the presentdisclosure. Therapy with the compounds or tautomers or pharmaceuticallyacceptable salts of said compounds or tautomers of the presentdisclosure may be initiated empirically before results of these testsare known; once results become available, antimicrobial therapy shouldbe adjusted accordingly.

To reduce the development of drug-resistant bacteria and maintain theeffectiveness of the compounds or tautomers or pharmaceuticallyacceptable salts of said compounds or tautomers of the presentdisclosure and other antibacterial drugs, the compounds or tautomers orpharmaceutically acceptable salts of said compounds or tautomers shouldbe used only to treat or prevent infections that are proven or stronglysuspected to be caused by susceptible bacteria. When culture andsusceptibility information are available, they should be considered inselecting or modifying antibacterial therapy. In the absence of suchdata, local epidemiology and susceptibility patterns may contribute tothe empiric selection of therapy.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection due to an aerobic or facultative gram-positivemicroorganism in a human or animal comprising administering to the humanor animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, or to the use of a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer, in the manufacture of a medicament for treating, preventing,reducing the risk of, or delaying the onset of a microbial infection dueto an aerobic or facultative gram-positive microorganism.

In some embodiments, the aerobic or facultative gram-positivemicroorganism is selected from: Staphylococcus aureus (methicillinsusceptible and resistant isolates), Streptococcus pneumoniae(penicillin susceptible and resistant isolates), Enterococcus spp.(vancomycin susceptible and resistant isolates), Streptococcusagalactiae, Streptococcus pyogenes, and Staphylococcus epidermidis(methicillin susceptible and resistant isolates).

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection due to an aerobic and facultative gram-negativemicroorganism in a human or animal comprising administering to the humanor animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, or to the use of a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer, in the manufacture of a medicament for treating, preventing,reducing the risk of, or delaying the onset of a microbial infection dueto an aerobic or facultative gram-positive microorganism.

In some embodiments, the aerobic and facultative gram-negativemicroorganism is selected from: Escherichia coli [including extendedspectrum beta-lactamase (ESBL) and Klebsiella pneumoniae (KPC) producingisolates), Haemophilus influenzae (including Beta-lactamase positiveisolates), Klebsiella pneumoniae (including ESBL and KPC producingisolates), Citrobacter freundii, Enterobacter aerogenes, Enterobactercloacae, Morganella morganii, Serratia marcescens, Pseudomonasaeruginosa, Acinetobacter baumanni, Moraxella catarrhalis, Proteusmirabilis, Citrobacter koseri, Haemophilus parainfluenzae, Klebsiellaoxytoca (including ESBL and KPC producing isolates), Proteus vulgaris,Providencia rettgeri, and Providencia stuartii.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection due to an anaerobic microorganism in a human oranimal comprising administering to the human or animal an effectiveamount of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or to theuse of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of a microbial infection due to an anaerobicmicroorganism.

In some embodiments, the anaerobic microorganism is selected from:Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus,Bacteroides thetaiotaomicron, Bacteroides uniformis, Clostridiumclostridioforme, Eubacterium lentum, Peptostreptococcus species,Porphyromonas asaccharolytica, Prevotella bivia, Bacteroides vulgates,Clostridium perfringens, and Fusobacterium spp.

In some embodiments, the present disclosure relates to a method oftreating or reducing the risk of a microbial infection in a human oranimal comprising administering to the human or animal an effectiveamount of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or to theuse of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of a microbial infection.

In some embodiments, the microorganism is Legionella pneumophilia.

In some embodiments, the microorganism Enterococcus spp. is selectedfrom vancomycin susceptible isolate and vancomycin resistant isolate. Insome embodiments, the microorganism Escherichia coli is selected fromextended spectrum beta-lactamase (ESBL) producing isolate and Klebsiellapneumoniae carbapenemase (KPC) producing isolate. In some embodiments,the microorganism Haemophilus influenzae is a beta-lactamase positiveisolate. In some embodiments, the microorganism Klebsiella pneumoniae isselected from extended spectrum beta-lactamase (ESBL) producing isolateand Klebsiella pneumoniae carbapenemase (KPC) producing isolate. In someembodiments, the microorganism Klebsiella oxytoca selected from extendedspectrum beta-lactamase (ESBL) producing isolate and Klebsiellapneumoniae carbapenemase (KPC) producing isolate. In some embodiments,the microorganism Staphylococcus aureus is selected from methicillinsusceptible isolate and methicillin resistant isolate. In someembodiments, the microorganism Staphylococcus epidermidis is selectedfrom methicillin susceptible isolate and methicillin resistant isolate.In some embodiments, the microorganism Streptococcus pneumoniae isselected from penicillin susceptible isolate and penicillin resistantisolate.

In some embodiments, a method or use disclosed herein is a method or useto treat a subject that would be subjected to a surgical or invasivemedical procedure. Such a subject can be considered to be in need of themethods of treating, reducing the risk of or preventing the infectiondue to a surgical procedure or an invasive medical procedure. Such asubject can also be considered to be in need of peri-operativeprophylaxis.

In some embodiments, the present disclosure relates to a method, use, orcompound disclosed herein, wherein the amount of compound or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer comprises from 0.1 mg to 1500 mg.

In some embodiments, the present disclosure relates to a method, use, orcompound disclosed herein wherein the compound, or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer, isadministered otically, ophthalmically, nasally, orally, parenterally,topically, or intravenously.

In some embodiments, the present disclosure relates to a method ofsynthesizing a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer.

In some embodiments, the present disclosure relates to a medical devicecontaining a compound disclosed herein or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer. In someembodiments, the device is a stent.

-   3. Synthesis of the Compounds of the Disclosure

The compounds of the present disclosure can be synthesized by using artrecognized techniques, such as those described in US 2012-0220566, WO2012/173689, or PCT/US2014/054869, the contents of each of which areincorporated herein by reference in their entireties. The compounds thusobtained can be further purified, for example, by flash columnchromatography, high performance liquid chromatography, crystallization,or any known purification method.

In one embodiment, the compounds of the present disclosure can besynthesized according to the synthetic Schemes 1-3 below:

Referring to scheme 1:

-   Step 1: Starting material (1) is protected with a suitable    protecting group (PG) (e.g., Cbz-C₁) to form (2). In some    embodiments, the reaction is carried out in a solvent (e.g.,    dichloromethane). In some embodiments, the reaction is carried out    is low temperature (e.g., 0° C.). In some embodiments, the reaction    is carried out in the presence of a base (e.g., sodium bicarbonate).-   Step 2: Intermediate (2) is reacted with SOCl₂ to obtain the    sulfinyl intermediate. In some embodiments, the reaction is carried    out in anhydrous dichloromethane. In some embodiments, the reaction    is carried out at −60° C. In some embodiments, the reaction is    carried out in the presence of imidazole. The sulfinyl intermediate    is reacted with the catalyst RuCl₃ in the presence of NaIO₄ to    obtain (3).-   Step 3: Intermediate (3) is reacted with (3a) to obtain (4). In some    embodiments, the reaction is carried out in a solvent (e.g., DMF).    In some embodiments, the reaction is carried out in the presence of    a base (e.g., NaH). In some embodiments, (3a) is made from nosyl    chloride and allyl amine.-   Step 4: Intermediate (4) is reacted with ethyl acrylate to yield    (5). In some embodiments, the reaction is carried out in anhydrous    dichloromethane. In some embodiments, the reaction is carried out in    the presence of Hoveyda-Grubbs 2^(nd) generation catalyst. n some    embodiments, the reaction is carried out at a temperature from about    25° C. to about 65° C. (e.g., 45° C.).-   Step 5: Intermediate (5) is reacted with trifluoromethanesulfonic    acid to obtain (6a) and (6b). In some embodiments, the reaction is    carried out in anhydrous dichloromethane at −78° C. In some    embodiments, the reaction is carried out in the presence of    triethylamine.-   Step 6: Intermediate (6a) is reacted with thiophenol to yield (7).    In some embodiments, the reaction is carried out in anhydrous DMF.    In some embodiments, the reaction is carried out in the presence of    a base (e.g., cesium carbonate).-   Step 7: Intermediate (7) is reacted with a protecting group (e.g.,    Boc₂O) to yield (8).-   Step 8: Intermediate (8) is reacted with a reducing reagent (e.g.,    LiBH₄ or LiEt₃BH) to obtain (9). In some embodiments, the reaction    is carried out in anhydrous THF at about 0° C.-   Step 9: Intermediate (9) is reacted with an azide-containing reagent    to yield (10). In some embodiments, azide-containing reagent    diphenylphosphoryl azide (DPPA). In some embodiments, the reaction    is carried out in the presence of a base (e.g., DBU).-   Step 10: Intermediate (10) is reduced and isolated as Boc-protected    derivative (11).-   Strep 11: Intermediate (11) is reacted with saturated solution of    sodium bicarbonate and a protecting group (e.g., Cbz-Cl) to yield    12.-   Step 12: Intermediate (12) is reacted with bispinacolatodiborane to    yield (13). In some embodiments, the reaction is carried out in the    presence of a catalyst (e.g., PdCl₂(dppf).CH₂C₂) and a base (e.g.,    potassium acetate).-   Step 13: Intermediate (13) is reacted with 5-iodocytosine to yield    the free-amine intermediate. In some embodiments, the reaction is    carried out in the presence of copper acetate monohydrate and    tetramethylehtylenediamine. The free-amine intermediate is reacted    with a protecting group (e.g., benzoic anhydride) to yield (15).-   Step 14: Intermediate (15) is reacted with alkyne (14) under    Sonogashira conditions to yield the protected intermediate. In some    embodiments, the reaction is carried out in presence of    N-N-diisopropylethylamine, Pd(PPh3)4 and CuI in DMF. The protected    intermediate is hydrolyzed with methanol to yield (16).-   Step 15: Intermediate (16) is deprotected under acidic conditions    (e.g., HCl) to yield the free-amine intermediate. The free-amine    intermediate is reacted with Bis-boc-1-pyrazolecarboxamide in the    presence of N-N-diisopropylethylamine to yield the protected    guanidine intermediate. The protected guanidine intermediate was    reacted with trifluoroacetic acid (TFA) to yield (17). In some    embodiments, the reaction is carried out in the presence of    thioanisole.

In some embodiments, intermediate 6b (Scheme 1) was converted to (18) asshown in scheme 2 using methods and procedures outlined in Scheme 1(Compounds 17 and 18 are diastereomers).

In some embodiments, intermediate (14) may be synthesized as describedin

Scheme 3.

Referring to Scheme 3:

Step 1: Alcohol (30) is reacted with an azide-containing reagent toobtain an azide (31). In some embodiments, the azide-containing reagentis NaN₃. In some embodiments, the alcohol (30) is reacted withmethanesulfonyl chloride prior to reaction with NaN₃.

Step 2: The azide (31) is reacted with triphenylphosphine to reduce theazide group and obtain the free amine-containing intermediate. Thefree-amine containing intermediate is reacted with a protecting group(e.g., Cbz-Cl) to yield (32).

Step 3: Alkene (32) is reacted with a boron reagent (e.g., 9-BBN) toobtain a boron intermediate which is further reacted with bromobenzene(33) to yield (34). In some embodiments, the reaction in carried out inthe presence of a catalyst (e.g., Pd(PPh₃)₄). In some embodiments, thereaction is carried out at a temperature from about 40° C. to about 80°C. (e.g., about 60° C.).

Step 4: bromobenzene (34) is reacted with an acetylene reagent (e.g.,TMS-acetylene) to yield (14). In some embodiments, the reaction iscarried out in the presence of a base (e.g., K₂CO₃).

In some embodiments, intermediate 14 can be prepared using methods andprocedures analogous to those described in PCT/US2014/054869 and U.S.provisional application 61/875,643, the disclosures of which areincorporated herein by reference in their entirety.

The specific approaches and compounds shown in the schemes above are notintended to be limiting. The chemical structures in the schemes hereindepict variables that are hereby defined commensurately with chemicalgroup definitions (moieties, atoms, etc.) of the corresponding positionin the compound formulae herein, whether identified by the same variablename (i.e., R₁, R₂, R₃, etc.) or not. The suitability of a chemicalgroup in a compound structure for use in the synthesis of anothercompound is within the knowledge of one of ordinary skill in the art.

Additional methods of synthesizing compounds of the formulae herein andtheir synthetic precursors, including those within routes not explicitlyshown in schemes herein, are within the means of chemists of ordinaryskill in the art. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe applicable compounds are known in the art and include, for example,those described in Larock R, Comprehensive Organic Transformations, VCHPublishers (1989); Fieser L et al., Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and Paquette L, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995) and subsequent editions thereof.

4. Characterization of Compounds of the Disclosure

Compounds designed, selected and/or optimized by methods describedabove, once produced, can be characterized using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules can becharacterized by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysisusing such assays. As a result, it can be possible to rapidly screen themolecules disclosed herein for activity, for example, as anti-cancer,anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also,it can be possible to assay how the compounds interact with a ribosomeor ribosomal subunit and/or are effective as modulators (for example,inhibitors) of protein synthesis using techniques known in the art.General methodologies for performing high-throughput screening aredescribed, for example, in Devlin (1998) High Throughput Screening,Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto, those described below.

(1) Surface Binding Studies. A variety of binding assays can be usefulin screening new molecules for their binding activity. One approachincludes surface plasmon resonance (SPR) that can be used to evaluatethe binding properties of molecules of interest with respect to aribosome, ribosomal subunit or a fragment thereof.

SPR methodologies measure the interaction between two or moremacromolecules in real-time through the generation of aquantum-mechanical surface plasmon. One device, (BIAcore Biosensor RTMfrom Pharmacia Biosensor, Piscataway, N.J.) provides a focused beam ofpolychromatic light to the interface between a gold film (provided as adisposable biosensor “chip”) and a buffer compartment that can beregulated by the user. A 100 nm thick “hydrogel” composed ofcarboxylated dextran that provides a matrix for the covalentimmobilization of analytes of interest is attached to the gold film.When the focused light interacts with the free electron cloud of thegold film, plasmon resonance is enhanced. The resulting reflected lightis spectrally depleted in wavelengths that optimally evolved theresonance. By separating the reflected polychromatic light into itscomponent wavelengths (by means of a prism), and determining thefrequencies that are depleted, the BIAcore establishes an opticalinterface which accurately reports the behavior of the generated surfaceplasmon resonance. When designed as above, the plasmon resonance (andthus the depletion spectrum) is sensitive to mass in the evanescentfield (which corresponds roughly to the thickness of the hydrogel). Ifone component of an interacting pair is immobilized to the hydrogel, andthe interacting partner is provided through the buffer compartment, theinteraction between the two components can be measured in real timebased on the accumulation of mass in the evanescent field and itscorresponding effects of the plasmon resonance as measured by thedepletion spectrum. This system permits rapid and sensitive real-timemeasurement of the molecular interactions without the need to labeleither component.

(2) Fluorescence Polarization. Fluorescence polarization (FP) is ameasurement technique that can readily be applied to protein-protein,protein-ligand, or RNA-ligand interactions in order to derive IC₅os andKds of the association reaction between two molecules. In this techniqueone of the molecules of interest is conjugated with a fluorophore. Thisis generally the smaller molecule in the system (in this case, thecompound of interest). The sample mixture, containing both theligand-probe conjugate and the ribosome, ribosomal subunit or fragmentthereof, is excited with vertically polarized light. Light is absorbedby the probe fluorophores, and re-emitted a short time later. The degreeof polarization of the emitted light is measured. Polarization of theemitted light is dependent on several factors, but most importantly onviscosity of the solution and on the apparent molecular weight of thefluorophore. With proper controls, changes in the degree of polarizationof the emitted light depends only on changes in the apparent molecularweight of the fluorophore, which in-turn depends on whether theprobe-ligand conjugate is free in solution, or is bound to a receptor.Binding assays based on FP have a number of important advantages,including the measurement of IC₅₀S and Kds under true homogenousequilibrium conditions, speed of analysis and amenity to automation, andability to screen in cloudy suspensions and colored solutions.

(3) Protein Synthesis. It is contemplated that, in addition tocharacterization by the foregoing biochemical assays, the compound ofinterest can also be characterized as a modulator (for example, aninhibitor of protein synthesis) of the functional activity of theribosome or ribosomal subunit.

Furthermore, more specific protein synthesis inhibition assays can beperformed by administering the compound to a whole organism, tissue,organ, organelle, cell, a cellular or subcellular extract, or a purifiedribosome preparation and observing its pharmacological and inhibitoryproperties by determining, for example, its inhibition constant (IC₅₀)for inhibiting protein synthesis. Incorporation of ³H leucine or ³⁵Smethionine, or similar experiments can be performed to investigateprotein synthesis activity. A change in the amount or the rate ofprotein synthesis in the cell in the presence of a molecule of interestindicates that the molecule is a modulator of protein synthesis. Adecrease in the rate or the amount of protein synthesis indicates thatthe molecule is an inhibitor of protein synthesis.

(4) Antimicrobial assays and other evaluation. Furthermore, thecompounds can be assayed for anti-proliferative or anti-infectiveproperties on a cellular level. For example, where the target organismis a microorganism, the activity of compounds of interest can be assayedby growing the microorganisms of interest in media either containing orlacking the compound. Growth inhibition can be indicative that themolecule can be acting as a protein synthesis inhibitor. Morespecifically, the activity of the compounds of interest againstbacterial pathogens can be demonstrated by the ability of the compoundto inhibit growth of defined strains of human pathogens. For thispurpose, a panel of bacterial strains can be assembled to include avariety of target pathogenic species, some containing resistancemechanisms that have been characterized. Use of such a panel oforganisms permits the determination of structure-activity relationshipsnot only in regards to potency and spectrum, but also with a view toobviating resistance mechanisms.

(5) The translation-only assay for ribosomal protein production usespurified 70S ribosomes, corresponding S100 extracts containing thebiological molecules necessary to support protein translation, and mRNAencoding firefly luciferase or another protein reporter. The resultingluminescence signal is proportional to protein translation and isdetermined by a luminescence assay plate reader (i.e. Victor2VMultilabel Reader). This assay is performed with varying concentrationsof potential translation inhibitors in the assay. The resulting data areused to calculate IC50 values of inhibition for the compounds usingappropriate software (i.e. MDL Assay Explorer with a one-sitecompetition model of binding).

The in vitro activity of the compounds of the present disclosure can bedetermined. Antimicrobial testing is typically performed to determinethe minimum inhibitory concentration (MIC). Minimum inhibitoryconcentrations (MICs) are determined by the microdilution method in afinal volume of 100 μl according to protocols outlined by The Clinicaland Laboratory Standards Institute (CLSI). Performance standards forreference strains are assessed within the same experimental design tomaintain quality control. See, for example, Clinical LaboratoryStandards Institute: Methods for dilution antimicrobial susceptibilitytests for bacteria that grow aerobically M7-A8. Approved Standard-EighthEdition. Wayne, Pa.: CLSI; December 2008; and Clinical LaboratoryStandards Institute: Performance Standards for AntimicrobialSusceptibility Testing M100-S20; Approved Standard-Twentieth Edition.Wayne, Pa.: CLSI; June 2010.

For example, an agar-dilution MIC assay could be run using the followingprotocol. Pure cultures of isolates to be tested are grown on ChocolateAgar at 35° C. to 36.5° C. in a CO₂ enriched (5%) atmosphere for 16-18hours. Using a cotton applicator or a bacteriologic loop, isolatedcolonies (or cells from less dense areas of growth on the plate) aresuspended in 5 mL saline. The density of the suspension is then adjustedto contain 10⁸ colony forming units (CFU)/ml by comparison with a 0.5McFarland BaSO₄ turbidity standard. This suspension is then diluted in1:10 in MH broth to give 10⁷ CFU/ml. Using a multichannel pipettor,0.002 mL spots of the bacterial suspension is dispensed onto the surfaceof the medium, i.e., 10⁴ CFU. Each plate of the set of antibioticcontaining media plus a plate of Chocolate Agar or GCS medium (as acontrol to determine that all isolates grew) is inoculated. Theinoculated plates are air-dried at room temperature for approximately 15minutes. The plates are then inverted and incubated at 35° C. to 36.5°C. in a CO₂-enriched (5%) atmosphere for 24 hours. The plates are thenexamined for growth.

Another in vitro assay that can be performed is a time-kill kineticassay. Using this assay, bactericidal activity can be determined bytime-kill methodology as described by Clinical Laboratory StandardsInstitute. For example, the compounds to be tested are added to testflasks at concentrations of 2×-32× the MIC (determined, for example,using the assays described herein). Once dissolved, compounds arediluted in Giolitti Cantoni (GC) broth to a volume of 1 mL at the 25×desired final concentration; a flask containing 1 mL of GC broth withoutcompound is prepared as a growth control. A 0.5 McFarland equivalent isprepared for the test organism, diluted 1:200 in pre-warmed GC broth,and incubated in 5% CO₂-enriched atmosphere at 35° C. for 30 minutesprior to exposure to the test compound. After the 30-minutepre-incubation, 24 mL is removed and added to each test flask for afinal volume of 25 mL. A sample is removed from the growth controlflask, diluted in Phosphate Buffered Saline (PBS) and plated onChocolate Agar (CA) to confirm an inoculum of approximately 5×10⁵CFU/mL. Samples are then removed from all flasks at 1, 2, 4, 6, 8, and24 hours, diluted in PBS and plated on CA to determine the number ofviable cells in each flask. Plate counts are incubated at 35° C. in 5%CO₂-enriched atmosphere for 48 hours and colonies are counted. Platecounts are then graphed.

The antimicrobial and other drug properties of the compounds can furtherbe evaluated in various in vivo mammalian assays, such as a mouse or ratperitonitis infectious models, skin and soft tissue models (oftenreferred to as the thigh model), or a mouse pneumonia model. There aresepticemia or organ infection models known to those skilled in the art.These efficacy models can be used as part of the evaluation process andcan be used as a guide of potential efficacy in humans. Endpoints canvary from reduction in bacterial burden to lethality. For the latterendpoint, results are often expressed as a PD₅₀ value, or the dose ofdrug that protects 50% of the animals from mortality.

To further assess a compound's drug-like properties, measurements ofinhibition of cytochrome P450 enzymes and phase II metabolizing enzymeactivity can also be measured either using recombinant human enzymesystems or more complex systems like human liver microsomes. Further,compounds can be assessed as substrates of these metabolic enzymeactivities as well. These activities are useful in determining thepotential of a compound to cause drug-drug interactions or generatemetabolites that retain or have no useful antimicrobial activity.

To get an estimate of the potential of the compound to be orallybioavailable, one can also perform solubility and Caco-2 assays. Thelatter is a cell line from human epithelium that allows measurement ofdrug uptake and passage through a Caco-2 cell monolayer often growingwithin wells of a 24-well microtiter plate equipped with a 1 micronmembrane. Free drug concentrations can be measured on the basolateralside of the monolayer, assessing the amount of drug that can passthrough the intestinal monolayer. Appropriate controls to ensuremonolayer integrity and tightness of gap junctions are needed. Usingthis same system one can get an estimate of P-glycoprotein mediatedefflux. P-glycoprotein is a pump that localizes to the apical membraneof cells, forming polarized monolayers. This pump can abrogate theactive or passive uptake across the Caco-2 cell membrane, resulting inless drug passing through the intestinal epithelial layer. These resultsare often done in conjunction with solubility measurements and both ofthese factors are known to contribute to oral bioavailability inmammals. Measurements of oral bioavailability in animals and ultimatelyin man using traditional pharmacokinetic experiments will determine theabsolute oral bioavailability.

Experimental results can also be used to build models that help predictphysical-chemical parameters that contribute to drug-like properties.When such a model is verified, experimental methodology can be reduced,with increased reliance on the model predictability.

(5) Animal Pharmacology and Toxicology. The compounds of the presentdisclosure can be evaluated for efficacy in well-known animal models.The following table provides representative animal models for variousinfection indications.

Target Infection Indication Animal Model of Efficacy HAP/VAP Efficacy inmouse and/or rat pneumoniae model vs. respiratory tract infectionpathogens of interest (Streptococcus pneumoniae, including multi-drugresistant Streptococcus pneumoniae, H. influenzae, methicillin resistantStaphylococcus aureus (MRSA), and Pseudomonas. aeruginosa) cSSSIEfficacy in mouse model against pathogens of interest (MRSA, K.pneumoniae) Sepsis Efficacy in mouse peritonitis model vs. pathogens ofinterest (E. coli, K. pneumoniae, E. faecalis, MRSA) cUTI Efficacy inmouse model against E. coli, K. pneumoniae and/or MRSA) Febrile Efficacyin mouse peritonitis model against S. aureus, S. neutropeniaepidermidis, S. pneumoniae, S. pyogenes, P. aeruginosa

-   Animal Model for Complicated Skin and Skin Structure Infections    (cSSSI): Murine Skin and Soft Tissue Infection Model of Klebsiella    pneumoniae 1705966 in Thighs of Neutropenic Female CD-1 Mice

This model is useful to assess the efficacy of compounds of the presentdisclosure in a Klebsiella pneumoniae 1705966 neutropenic mouse thighinfection model using female ICR (CD-1) mice.

Study Design:

Species: Female ICR (CD-1) Mice, 8 to 9 weeks old, weighting 25-29 g.

Inoculum: Klebsiella pneumoniae 17059663 was streaked from frozen stockonto Blood agar (Tryptic Soy Agar+5% Sheep Blood), BD, #221261) andincubated overnight at 35° C. After overnight incubation, enoughbacteria (approx. 1 full loop) to measure OD₆₂₅=0.990 was transferredfrom plate and diluted into 10 ml pre-warmed Mueller-Hinton broth. Thisculture was further diluted 1:1000 into pre-warmed MH broth and grownfor approximately 2 hours at 35° C. with shaking. Each mouse was given0.1 mL of 1:1000 dilution culture injected into both caudal thighmuscles under isoflurane inhalation anesthesia.

Final O.D. Initial (after~2 hr. Dilution O.D. incubation) 1:10 0.1350.424 1:100 0.014 0.215 1:1000 0.001 0.035

-   Neutropenia is induced by intraperitoneal (I.P.) administration of    Cyclophosphamide monohydrate on Day −4 (150 mg/kg) and Day −1 (100    mg/kg).

Vehicle: 0.9% sodium chloride

Dosing: Each mouse in the treated groups was given the appropriate doseof the compound to be tested in a volume of 0.2 m1, 2 and 8 hrs. postbacterial inoculation.

Time points:

Controls: 0, 2, 6, and 24 hrs.

Treated: 24 hrs.

Sampling: 2 or 3 mice/time point were euthanized via CO₂, and theircaudal thigh muscles excised and homogenized. The thigh muscles wereplaced in 5 ml sterile PBS in Stomacher Filter bag and homogenized withMicroBiomaster80 (Brinkmann) for 60 seconds, normal setting and 1:10dilutions were made per standard protocol in a 96-well plate. Aliquotsof 25 μl for each dilution, as well as the homogenate, were plated onblood agar plates and incubated at 35° C. to determine the CFU/mL overthe time course. After overnight incubation, colonies were counted.

Animal Model for Sepsis:

-   Murine peritonitis model (E. coli, K. pneumoniae, E. faecalis, MRSA)

This model is used to evaluate the effect of subcutaneous (SC) treatmentwith compounds of the present disclosure on growth of Escherichia coliATCC 25922 in a mouse peritonitis model using female Swiss Webster mice.

-   Controls:

Negative: Inoculum only

Inoculum Vehicle Intraperitoneal

Positive: Ciprofloxacin

-   Study Design:

Species: Female Swiss Webster Mice

Inoculation: Escherichia coli ATCC 25922 is made by adding 1 ml (4/6/07)stock to 9 ml 0.25% Brewer's Yeast to make (1:10), then lml of the(1:10) will be added to 9 ml 0.25% Brewer's Yeast to make (1:100), thenlml of the (1:100) will be added to 9 ml 0.25% Brewer's Yeast to make(1:1000), then 2.5 ml of the (1:1000) will be added to 122.5 ml 0.25%Brewer's Yeast to make (1:50,000), 1 ml/mouse will be inoculatedintraperitoneally (IP).

Route of Administration: SC

Dosing: Vehicle for compounds of the present disclosure: Saline or 50 mMSodium phosphate buffer in 10% Captisol in water, pH=7.2.

Dose Administration: Q3H×3 beginning at 30 min post bacterialinoculation Study Duration: 24 hrs. 0.25% Brewer's Yeast Extract (BYE):Dilute 2% prepared on Nov. 12, 2009 (Lot.2158K, MP Biomedicals) 25 ml2%+175 ml 1×PBS.

Outcome Measures: Colony Forming Unit's from peritoneal wash and spleenhomogenate and drug levels from wash, spleen homogenate, and plasma.

Blood is collected via cardiac puncture while mouse is under CO₂narcosis. The whole blood sample is placed in heparinized eppendorftubes and kept on wet ice until centrifuged (4 min @ 14,000 rpm). Plasmais transferred to 96 deep-well block on dry ice and stored at −20° C.Immediately following blood collection, 2 ml of sterile PBS (phosphatebuffered saline) was injected into the peritoneal cavity with a 25 Gneedle. The abdomen was gently massaged, and a small incision was madeto allow access to the peritoneal cavity. The peritoneal wash fluid wascollected using sterile technique, serially diluted 1:10, plated onblood agar plates, and incubated overnight at 35° C.

Spleens were harvested and placed in 1 ml sterile PBS in Stomacher bagand homogenized with MicroBiomaster80 (Brinkmann) for 60 seconds, normalsetting and 1:10 dilutions were made. 25 μl of each dilution, as well asthe homogenate, was plated on blood agar plates and incubated at 35° C.to determine the CFU/mL over the time course. After overnightincubation, colonies were counted.

Other Animal Models

Similarly, other animal infection models can be used for hospitalacquired pneumonia (HAP)/ventilator acquired pneumonia (VAP),complicated urinary tract infections (cUTI), and febrile neutropenia.

-   5. Formulation and Administration

The compositions and methods of the present disclosure can be practicedby delivering the compounds of the present disclosure using a means fordelivery e.g., any suitable carrier. The dose of active compound, modeof administration and use of suitable carrier will depend upon theintended patient or subject and the targeted microorganism, e.g., thetarget bacterial organism. The formulations, both for human medical useand veterinary use, of compounds according to the present disclosuretypically include such compounds in association with a pharmaceuticallyacceptable carrier.

The carrier(s) should be “acceptable” in the sense of being compatiblewith compounds of the present disclosure and not deleterious to therecipient. Pharmaceutically acceptable carriers, in this regard, areintended to include any and all solvents, dispersion media, coatings,absorption delaying agents, and the like, compatible with pharmaceuticaladministration. Supplementary active compounds (identified or designedaccording to the disclosure and/or known in the art) also can beincorporated into the compositions. In some embodiments, someformulations are prepared by bringing the compound into association witha liquid carrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

A pharmaceutical composition of the disclosure should be formulated tobe compatible with its intended route of administration. Solutions orsuspensions can include the following components: a sterile diluent suchas water, saline solution, fixed oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents; antibacterial agents suchas benzyl alcohol or methyl parabens; antioxidants such as ascorbic acidor sodium bisulfite; chelating agents such as ethylenediaminetetraaceticacid; buffers such as acetates, citrates or phosphates and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

Formulations for parenteral administration can also include glycocholatefor buccal administration, methoxysalicylate for rectal administration,or citric acid for vaginal administration. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic. Suppositories for rectal administration alsocan be prepared by mixing the drug with a non-irritating excipient suchas cocoa butter, other glycerides, or other compositions which are solidat room temperature and liquid at body temperatures. Formulations alsocan include, for example, polyalkylene glycols such as polyethyleneglycol, oils of vegetable origin, and hydrogenated naphthalenes.Formulations for direct administration can include glycerol and othercompositions of high viscosity. Other potentially useful parenteralcarriers for these drugs include ethylene-vinyl acetate copolymerparticles, osmotic pumps, implantable infusion systems, and liposomes.Formulations for inhalation administration can contain as excipients,for example, lactose, or can be aqueous solutions containing, forexample, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate,or oily solutions for administration in the form of nasal drops, or as agel to be applied intranasally. Retention enemas also can be used forrectal delivery.

Formulations of the present disclosure suitable for oral administrationcan be in the form of: discrete units such as capsules, gelatincapsules, sachets, tablets, troches, or lozenges, each containing apredetermined amount of the drug; a powder or granular composition; asolution or a suspension in an aqueous liquid or non-aqueous liquid; oran oil-in-water emulsion or a water-in-oil emulsion. The drug can alsobe administered in the form of a bolus, electuary or paste. A tablet canbe made by compressing or molding the drug optionally with one or moreaccessory ingredients. Compressed tablets can be prepared bycompressing, in a suitable machine, the drug in a free-flowing form suchas a powder or granules, optionally mixed by a binder, lubricant, inertdiluent, surface active or dispersing agent. Molded tablets can be madeby molding, in a suitable machine, a mixture of the powdered drug andsuitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients. Oral compositions preparedusing a fluid carrier for use as a mouthwash include the compound in thefluid carrier and are applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). Itshould be stable under the conditions of manufacture and storage andshould be preserved against the contaminating action of microorganismssuch as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (for example,glycerol, propylene glycol, and liquid polyethylene glycol), andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. In many cases, it will be preferable to include isotonicagents, for example, sugars, polyalcohols such as mannitol, sorbitol,and sodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfilter sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation include vacuumdrying and freeze-drying which yields a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Formulations suitable for intra-articular administration can be in theform of a sterile aqueous preparation of the drug that can be inmicrocrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems can also be used to present the drug for bothintra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eyetreatment, include liquid or semi-liquid preparations such as liniments,lotions, gels, applicants, oil-in-water or water-in-oil emulsions suchas creams, ointments or pastes; or solutions or suspensions such asdrops. Formulations for topical administration to the skin surface canbe prepared by dispersing the drug with a dermatologically acceptablecarrier such as a lotion, cream, ointment or soap. Useful are carrierscapable of forming a film or layer over the skin to localize applicationand inhibit removal. For topical administration to internal tissuesurfaces, the agent can be dispersed in a liquid tissue adhesive orother substance known to enhance adsorption to a tissue surface. Forexample, hydroxypropylcellulose or fibrinogen/thrombin solutions can beused to advantage. Alternatively, tissue-coating solutions, such aspectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling orspray formulations) dispensed with a spray can, a nebulizer, or anatomizer can be used. Such formulations can be in the form of a finepowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations. In the case ofself-propelling solution and spray formulations, the effect can beachieved either by choice of a valve having the desired spraycharacteristics (i.e., being capable of producing a spray having thedesired particle size) or by incorporating the active ingredient as asuspended powder in controlled particle size. For administration byinhalation, the compounds also can be delivered in the form of anaerosol spray from pressured container or dispenser which contains asuitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants include, for example, for transmucosal administration,detergents and bile salts. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds typically areformulated into ointments, salves, gels, or creams.

The active compounds can be prepared with carriers that will protect thecompound against rapid elimination from the body, such as a controlledrelease formulation, including implants and microencapsulated deliverysystems. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Liposomal suspensions can also beused as pharmaceutically acceptable carriers.

Oral or parenteral compositions can be formulated in dosage unit formfor ease of administration and uniformity of dosage. Dosage unit formrefers to physically discrete units suited as unitary dosages for thesubject to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the disclosure are dictated by and directlydependent on the unique characteristics of the active compound and thetherapeutic effect to be achieved, and the limitations inherent in theart of compounding such an active compound for the treatment ofindividuals. Furthermore, administration can be by periodic injectionsof a bolus, or can be made more continuous by intravenous, intramuscularor intraperitoneal administration from an external reservoir (e.g., anintravenous bag).

Where adhesion to a tissue surface is desired the composition caninclude the drug dispersed in a fibrinogen-thrombin composition or otherbioadhesive. The compound then can be painted, sprayed or otherwiseapplied to the desired tissue surface. Alternatively, the drugs can beformulated for parenteral or oral administration to humans or othermammals, for example, in effective amounts, e.g., amounts that provideappropriate concentrations of the drug to target tissue for a timesufficient to induce the desired effect.

Where the active compound is to be used as part of a transplantprocedure, it can be provided to the living tissue or organ to betransplanted prior to removal of tissue or organ from the donor. Thecompound can be provided to the donor host. Alternatively, or, inaddition, once removed from the donor, the organ or living tissue can beplaced in a preservation solution containing the active compound. In allcases, the active compound can be administered directly to the desiredtissue, as by injection to the tissue, or it can be providedsystemically, either by oral or parenteral administration, using any ofthe methods and formulations disclosed herein. Where the drug comprisespart of a tissue or organ preservation solution, any commerciallyavailable preservation solution can be used to advantage. For example,useful solutions known in the art include Collins solution, Wisconsinsolution, Belzer solution, Eurocollins solution and lactated Ringer'ssolution.

Generally, an effective amount of dosage of active compound will be inthe range of from about 0.1 to about 100 mg/kg of body weight/day, morepreferably from about 1.0 to about 50 mg/kg of body weight/day. Theamount administered will also likely depend on such variables as thetype of surgery or invasive medical procedure, the overall health statusof the patient, the relative biological efficacy of the compounddelivered, the formulation of the drug, the presence and types ofexcipients in the formulation, and the route of administration. Also, itis to be understood that the initial dosage administered can beincreased beyond the above upper level in order to rapidly achieve thedesired blood-level or tissue level, or the initial dosage can besmaller than the optimum.

Nonlimiting doses of active compound comprise from about 0.1 to about1500 mg per dose.

As is understood by one of ordinary skill in the art, generally, whendosages are described for a pharmaceutical active, the dosage is givenon the basis of the parent or active moiety. Therefore, if a salt,hydrate, or another form of the parent or active moiety is used, acorresponding adjustment in the weight of the compound is made, althoughthe dose is still referred to on the basis of the parent or activemoiety delivered. As a nonlimiting example, if the parent or activemoiety of interest is a monocarboxylic acid having a molecular weight of250, and if the monosodium salt of the acid is desired to be deliveredto be delivered at the same dosage, then an adjustment is maderecognizing that the monosodium salt would have a molecular weight ofapproximately 272 (i.e., minus 1 H or 1.008 atomic mass units and plus 1Na or 22.99 atomic mass units). Therefore, a 250 mg dosage of the parentor active compound would correspond to about 272 mg of the monosodiumsalt, which would also deliver 250 mg of the parent or active compound.Said another way, about 272 mg of the monosodium salt would beequivalent to a 250 mg dosage of the parent or active compound.

Formulation Examples

-   IA. Formulation for Intravenous Administration

Ingredients Amount Antimicrobial Compound 0.1-1500 total mg of thepresent disclosure Dextrose, USP 50 mg/ml Sodium citrate, USP 1.60-1.75mg/ml Citric Acid, USP 0.80-0.90 mg/ml Water, USP q.s

This formulation for intravenous administration is formulated by heatingwater for injection to about 60° C. Next the sodium citrate, citric acidand dextrose are added and stirred until dissolved. A solution oraqueous slurry of the antimicrobial compound is added to the previousmixture and stirred until dissolved. The mixture is cooled to 25° C.with stirring. The pH is measured and adjusted if necessary. Lastly themixture is brought to the desired volume, if necessary, with water forinjection. The mixture is filtered, filled into the desired container(vial, syringe, infusion container, etc.), over wrapped and terminallymoist heat sterilized.

This formulation is useful for intravenous administration, either bolusor infusion, to a patient for treating, preventing, reducing the riskof, or delaying the onset of infection.

IB. Formulation for Intravenous Administration

This formulation for intravenous administration utilizes 6.5 nM tartaricacid buffer in 5% Dextrose, and has a pH of 4.4. This formulation isuseful for intravenous administration, either bolus or infusion, to apatient for treating, preventing, reducing the risk of, or delaying theonset of infection.

-   II Lyophilisate for Reconstitution

Alternatively, the antimicrobial compound can be provided as alyophilisate which can be reconstituted before intravenous orintramuscular administration.

Ingredient mg per injection vial Antimicrobial Compound 0.1-1500 of thepresent disclosure Cyclodextrin 1500

Reconstitution solution for a volume to be administered of 50 ml(infusion): 5% aqueous glucose solution.

Reconstitution solution for a volume to be administered of 15 ml(bolus): 3.3% aqueous glucose solution.

The foregoing lyophilisate is useful for reconstitution and intravenousadministration, either bolus or infusion, to a patient for treating,preventing, reducing the risk of, or delaying the onset of infection.

-   III. Lyophilisate for Reconstitution

Ingredient mg per injection vial Antimicrobial Compound 0.1-1500 of thepresent disclosure soya lecithin 2250 Sodium cholate 1500

Reconstitution solution for a volume to be administered of 50 ml(infusion): 4% aqueous glucose solution.

Reconstitution solution for a volume to be administered of 15 ml(bolus): 2% aqueous glucose solution

The foregoing lyophilisate is useful for reconstitution and intravenousadministration, either bolus or infusion, to a patient for treating,preventing, reducing the risk of, or delaying the onset of infection.

-   IV. Lyophilisate for Reconstitution

Ingredient mg per injection vial Antimicrobial Compound 0.1-1500 of thepresent disclosure soya lecithin 900 Sodium glycocholate 540

Reconstitution solution for a volume to be administered of 15 ml(bolus): 3.3% aqueous glucose solution.

The foregoing lyophilisate is useful for reconstitution and intravenousadministration, either bolus or infusion, to a patient for treating,preventing, reducing the risk of, or delaying the onset of infection.

-   V. Tablet for Oral Administration

Per 4000 Ingredients Per Tablet Tablets Antimicrobial Compound 0.1-1500mg 0.4-6000 g of the present disclosure Anhydrous Lactose, NF 110.45 mg441.8 g Microcrystalline 80.0 mg 320.0 g Cellulose NF Magnesium Stearate1.00 mg 4.0 g Impalpable Powder NF Croscarmellose Sodium 2.00 mg 8.0 gNF Type A

The antimicrobial compound (any of the compounds equivalent to thedesired delivery strength, e.g., 50 to 1500 mg per tablet) is premixedwith ⅓ of the microcrystalline cellulose NF and ½ of the anhydrouslactose NF in a ribbon blender for 5 minutes at 20 RPM. To the premix isadded the remaining ⅔ of the microcrystalline cellulose NF and theremaining ½ of the anhydrous lactose NF. This is blended for 10 minutesat 20 RPM. Croscarmellose sodium is added to the blended powders andmixed for 5 minutes at 20 RPM. Finally the magnesium stearate is addedto the mixture by passing through a 90 mesh screen and blended for anadditional 5 minutes at 20 RPM. The lubricated mixture is compressed toprovide tablets of 500 mg active ingredient.

These tablets are useful for oral administration to a patient fortreating, prevention, reducing the risk of, or delaying the onset ofinfection.

6. EXAMPLES

Nuclear magnetic resonance (NMR) spectra were obtained on a BrukerAvance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300spectrometer. Common reaction solvents were either high performanceliquid chromatography (HPLC) grade or American Chemical Society (ACS)grade, and anhydrous as obtained from the manufacturer unless otherwisenoted. “Chromatography” or “purified by silica gel” refers to flashcolumn chromatography using silica gel (EM Merck, Silica Gel 60, 230-400mesh) unless otherwise noted.

The compounds or tautomers thereof, or pharmaceutically acceptable saltsof said compounds or tautomers of the present disclosure can be preparedusing known chemical transformations adapted to the particular situationat hand.

Some of the abbreviations used in the following experimental details ofthe synthesis of the examples are defined below: h or hr=hour(s);min=minute(s); mol=mole(s); mmol=millimole(s); M=molar; μM=micromolar;g=gram(s); μg=microgram(s); rt=room temperature; L=liter(s);mL=milliliter(s); Et₂O=diethyl ether; THF=tetrahydrofuran; DMSO=dimethylsulfoxide; EtOAc=ethyl acetate; Et₃N=triethylamine; i-Pr₂NEt orDIPEA=diisopropylethylamine; CH₂Cl₂=methylene chloride;CHCl₃=chloroform; CDCl₃=deuterated chloroform; CCl₄=carbontetrachloride; MeOH=methanol; CD₃OD=deuterated methanol; EtOH=ethanol;DMF=dimethylformamide; BOC=t-butoxycarbonyl; CBZ=benzyloxycarbonyl;TBS=t-butyldimethylsilyl; TBSCl=t-butyldimethylsilyl chloride;TFA=trifluoroacetic acid; DBU=diazabicycloundecene;TBDPSCl=t-butyldiphenylchlorosilane; Hunig'sBase=N,N-diisopropylethylamine; DMAP=4-dimethylaminopyridine; CuI=copper(I) iodide; MsCl=methanesulfonyl chloride; NaN₃=sodium azide;Na₂SO₄=sodium sulfate; NaHCO₃=sodium bicarbonate; NaOH=sodium hydroxide;MgSO₄=magnesium sulfate; K₂CO₃=potassium carbonate; KOH=potassiumhydroxide; NH₄OH=ammonium hydroxide; NH₄Cl =ammonium chloride;SiO₂=silica; Pd-C=palladium on carbon;Pd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium(II).

Exemplary compounds synthesized in accordance with the disclosure arelisted in Table 1, Table 1a, or Table 1b. A bolded or dashed bond isshown to indicate a particular stereochemistry at a chiral center,whereas a wavy bond indicates that the substituent can be in eitherorientation or that the compound is a mixture thereof.

The compounds of the present disclosure can be prepared, formulated, anddelivered as salts. For convenience, the compounds are generally shownwithout indicating a particular salt form.

The compounds of the present disclosure can be made using syntheticchemical techniques well known to those of skill in the art.

Example 1 Syntheses of Compounds 1-32

Compounds 1-32 may be prepared according to the methods and proceduressimilar to those described in Schemes 1-3 above as well as for thesynthesis of compound 23, which was synthesized according to the methodsdescribed below:

-   Synthetic scheme for Compound 23

Experimental (referring to synthetic scheme for Compound 23):

The suspension of 1 (3.00 g, 14 mmol) in dichloromethane (40 ml) wascooled down to 0° C., saturated solution of sodium bicarbonate (25 ml)was added followed by dropwise addition of Cbz-Cl (2.96 g, 16.8 mmol)and the mixture was stirred for 30 min. Cooling bath was removed and thereaction mixture was continued to stir for another 5 h. LCMS showed thecompletion of the reaction. Organic phase was separated, washed with 40ml of water, dried over sodium sulfate, concentrated and purified byflash chromatography (SiO₂ column, Heptane/Ethyl acetate gradient) toobtain 3.67 g (yield, 75%) of 2 as white solid. MS (ESI) m/z [M+Na]⁺;calcd for C₁₆H₁₆BrNNaO₃; 372.0, found 372.5.

To the solution of SOCl₂ (1.37 g, 11.5 mmol) in anhydrousdichloromethane (104 ml) at −60° C. under argon atmosphere weresequentially added triethylamine (2.20 g, 21.85 mmol) and imidazole(2.89 g, 42.5 mmol). After stirring for 30 min, the solution of 2 (3.66g, 10.46 mmol) in 25 ml of dichloromethane was added dropwise (in 10min) with vigorous stirring. It was continued to stir at the sametemperature for another 3 h. Cooling bath was removed and stirred foranother 1 h 45 min. 100 ml of water was added and reaction mixture wasstirred for 20 min. Organic phase was separated, washed with 100 ml ofwater, dried over sodium sulfate, concentrated to dryness, and purifiedby flash chromatography (SiO₂ column, heptane/Ethyl acetate gradient) toobtain 3.5 g of white solid which was dissolved in 90 ml ofacetonitrile, cooled to 0° C., NaIO4 (2.46 g, 11.5 mmol), RuCl_(3.3)H₂O(0.024 g, 0.115 mmol) and water (70 ml) were added sequentially. Themixture was stirred for 1 h when TLC showed completion of reaction.Another 70 ml of water was added, cooling bath was removed, stirred for40 min. White precipitation was observed. Product was extracted withdiethyl ether (120 ml×3). Combined organic phases was washed with water(100 ml) and brine (100 ml), dried over sodium sulfate and concentratedto dryness to obtain 3.85 g (yield, 89%) of 3 as a white solid. MS (ESI)m/z [M+Na]⁺; calcd for C₁₆H₁₄BrNNaO₅S ; 434.0, found 435.3.

Sodium hydride (1.00 g, 25 mmol, 60% in paraffin oil) was added to thesolution of 3a (made from nosyl chloride and allyl amine, 6.05 g, 25mmol) in anhydrous DMF (125 ml) under argon atmosphere. Stirred for 1 hupon which 3 (7.21 g, 17.5 mmol) was added and stirred for another 17 h.LCMS showed complete consumption of 3. Aqueous hydrochloric acid (17.5ml of 6 N solution) was added and reaction mixture was stirred for 1 h.pH was adjusted to 12.5 by adding saturated aqueous solution ofpotassium carbonate. 100 ml of water was added. Product was extractedwith dichloromethane (150 ml×2). Combined organic phases was washed withwater (150 ml), dried over sodium sulfate, concentrated and purified byflash chromatography (SiO₂ column, Heptane/Ethyl acetate gradient) toobtain 7.40 g (yield, 74%) of 4 as a white solid. MS (ESI) m/z [M+Na]⁻;calcd for C₂₅H₂₄BrN₃NaO₆S ; 596.0, found 596.4.

Ethyl acrylate (4.2 g, 42 mmol) was added to the solution of 4 (8.05 g,14 mmol) in anhydrous dichloromethane (93 ml). After stirring for 5 min,Hoveyda-Grubbs 2^(nd) generation catalyst (0.175 g, 0.28 mmol) wasadded. The mixture was stirred under argon at 45° C. for 5 h. LCMSshowed completion of the reaction. The mixture was concentrated andpurified by flash chromatography (SiO₂ column, Heptane/Ethyl acetategradient) to obtain 8.2 g (yield, 91%) of 5 as an off-white solid. MS(ESI) m/z [M+H]⁺; calcd for C₂₈H₂₈BrN3NaO8S ; 668.0, found 668.4.

Trifluoromethanesulfonic acid (3.9 g, 26 mmol) was added to solution of5 in 173.5 ml of anhydrous dichloromethane at −78° C. Cooling bath wasremoved, stirred for 5 h. LCMS showed complete removal of Cbz group. Itwas again cooled down to −78° C., triethylamine (2.6 g, 26 mmol) wasadded dropwise. The mixture was stirred for 30 min at −78° C., then itwas placed in ice-NaCl bath (about −10° C.), stirred for 1 h when LCMSshowed the complete consumption of Cbz-deprotected intermediate andformation of two products of same mass. 150 ml of water was addedorganic phase was separated washed with another 150 ml of water, driedover sodium sulfate, concentrated and purified by flash chromatography(SiO₂ column, Heptane/Ethyl acetate gradient) to obtain 1.05 g of 6a and1.20 g of 6b (combined yield 85%, both the isomers are white solid). MS(ESI) m/z [M+H]⁺; calcd for C₂₀H₂₃BrN₃O₆S ; 512.0, found 512.4.

To the solution of 6a (2.04 g, 4 mmol) in anhydrous DMF (40 ml) underargon atmosphere cesium carbonate (5.21 g, 16 mmol) was added andstirred for 10 min, followed by addition of thiophenol (0.88 g, 8 mmol).The mixture was left stirring for 14 h. LCMS showed completer removal ofnosyl group and formation of 7 and also trace amount oftrans-esterification with thiophenol. 40 ml of water and 40 ml of ethylacetate were added and the mixture was cooled down to 0° C. Boc₂O (0.86g, 4 mmol) was added to this cold mixture and the resultant mixture wasstirred for 5 h. LCMS showed the completion of mono Boc protection.Organic phase was separated, washed with water (20 ml×2) and brine (20ml), dried over sodium sulfate, concentrated and purified by flashchromatography (SiO₂ column, Heptane/Ethyl acetate gradient) to obtain1.37 g (yield, 84%) of 8 as a colorless sticky solid. MS (ESI) m/z[M+H]⁺; calcd for C₁₉H₂₈BrN₂O₄; 427.1, found 427.4.

The solution of 8 (1.38 g, 3.25 mmol) in anhydrous THF (16.25) wascooled to 0° C., LiBH₄ (0.149 g 90% pure, 6.5 mmol) was added slowly,followed by addition of LiEt₃BH (0.35 ml 1M solution in THF, 0.35 mmol).The mixture was stirred at that temperature for 1 h. Cooling bath wasremoved and stirring was continued for another 17 h. LCMS showedcomplete consumption of 8 and formation of alcohol 9. Reaction mixturewas cooled down to 0° C., 5 ml of water was added drop wise followed byaddition of another 20 ml of water. After 30 min cooling bath wasremoved and stirred at rt for 5 h. Organic phase was separated; aqueousphase was extracted with ethyl acetate 20 ml×2). Combined organic phaseswas washed with water (30 ml) and brine (30 ml), dried over sodiumsulfate, concentrated and purified by flash column chromatography (SiO₂,CH₂Cl₂/(90% CH₂Cl₂+9.8% methanol +0.2% NH₄OH)) to obtain 1.19 g (yield,95%) of 9 as a white solid. MS (ESI) m/z [M+H]⁺; calcd for C₁₇H₂₆BrN₂O₃;385.1, found 385.4.

To the stirring solution of 9 (1.15 g, 3 mmol) in anhydrous toluene (20ml) under argon atmosphere diphenylphosphoryl azide (1.15 g, 4.2 mmol)was added followed by dropwise addition of DBU (0.63 g, 4.2 mmol). After30 min, it was placed in 80° C. temperature oil bath and stirred for 14h. LCMS shows the completion of the reaction. Cooled down to roomtemperature, 20 ml of water is added and the product is extracted byEtOAc (20 ml×2). Combined organic phases was washed with water (25 ml)and brine (25 ml), dried over sodium sulfate, concentrated and purifiedby flash chromatography (silica gel column, Heptane/Ethyl acetategradient) to obtain 1.05 g (yield, 85%) of 10 as colorless sticky solid.MS (ESI) m/z [M+H]⁺; calcd for C₁₇H₂₅BrN₅O₂; 410.1, found 410.4.

To the stirring solution of 10 (1.02 g, 2.5 mmol) in THF (23 ml),triphenylphosphine (0.98 g, 3.75 mmol) and water (1.85 ml) were added.The mixture was stirred at 55° C. for 4 h. LCMS showed completereduction of azide to amine. The reaction mixture was cooled down to 0°C., Boc anhydride (0.65 g, 3 mmol) was added and the reaction mixturewas left stirring in the same bath overnight. LCMS showed completeconsumption of intermediate amine. It was concentrated in vacuo andpurified by flash silica gel chromatography (Heptane/Ethyl acetategradient) to obtain 1.01 g (yield, 84%) of 11 as white solid. MS (ESI)m/z [M+H]⁺; calcd for C₂₂H₃₅BrN₃O₄; 484.2, found 484.5.

The solution of 11 (1 g, 2.1 mmol) in dichloromethane (10.5 ml) wascooled down to 0° C., saturated solution of sodium bicarbonate (6.3 ml)was added followed by dropwise addition of Cbz-Cl (0.51 g, 2.94 mmol)and the mixture was stirred for 30 min. Cooling bath was removed andreaction mixture continued to stir for another 15 h. LCMS showed thecompletion of the reaction. Organic phase was separated, washed with 10ml of water, dried over sodium sulfate, concentrated and purified byflash chromatography (SiO₂ column, Heptane/Ethyl acetate gradient) toobtain 1.10 g (yield, 85%) of 12 as a white solid. MS (ESI) m/z [M+Na]⁺;calcd for C₃₀H₄₀BrN₃NaO₆; 640.2, found 640.6.

To the solution of 12 (1.10 g, 1.8 mmol) in anhydrous DMSO (12 ml),bispinacolatodiborane (0.92 g, 3.6 mmol), potassium acetate (0.62 g, 6.3mmol) and PdCl₂(dppf).CH₂Cl₂ (0.074 g, 0.09 mmol) were added. Themixture was degassed, purged with argon twice and stirred at 80° C. for14 h. LCMS showed complete consumption of 12 and formation of 13. Cooleddown to room temperature, 30 ml of water was added. Product wasextracted with ethyl acetate (40 ml×2). Combined organic phases werewashed with water (30 ml), 14% ammonium hydroxide (30 ml), water (40 ml)and brine (40 ml). It was dried over sodium sulfate, concentrated andpurified by flash silica gel chromatography (Heptane/Ethyl acetategradient) to obtain 1.14 g (yield, 95%) of 13 as a white solid. MS (ESI)m/z [M+Na]⁺; calcd for C₃₆H₅₂BN₃NaO₈; 688.37, found 688.8.

To the solution of 13 (1.14 g, 1.7 mmol) in methanol (25 ml), 7 ml ofwater was added. To this mixture were added 5-iodocytosine (0.57 g, 2.38mmol), copper acetate monohydrate (0.34 g, 1.7 mmol) followed bytetramethylehtylenediamine (0.41 g, 3.57 mmol). The mixture was stirredat room temperature under open air. After 19 h LCMS showed completeconsumption of 13. Methanol was evaporated. 30 ml of water was added.Product was extracted by ethyl acetate (40 ml×2). Combined organicphases was washed with water (40 ml), 14% ammonium hydroxide (40 ml),water (40 ml) and brine (40 ml), dried over sodium sulfate andconcentrated to dryness. The crude residue was dissolved in 32 ml ofethyl acetate, benzoic anhydride (0.47 g, 2.02 mmol) was added and themixture was stirred at 80° C. for 4 h. LCMS showed completion ofbenzoylation of the intermediate amine. Solvent was evaporated andpurified by flash chromatography (silica gel column, Heptane/Ethylacetate gradient) to obtain 1.2 g (yield, 80%) of 15 as a white solid.MS (ESI) m/z [M+H]⁺; calcd for C₄₁H₄₈IN₆O₈; 879.26, found 879.7.

The solution of 15 (0.61 g, 0.7 mmol) and alkyne 14 (0.26 g, 0.7 mmol)in anhydrous DMF (7 ml) was degassed and purged with argon twice. Tothis solution were added N-N-diisopropylethylamine (0.27 g, 2.1 mmol)followed by Pd(PPh₃)₄ (0.040 g, 0.035 mmol) and CuI (0.0134 g, 0.07mmol). The mixture was stirred at 70 ° C. for 12 h. LCMS showedcompletion of Sonogashira coupling. The reaction mixture was cooled downto room temperature, 7 ml of methanol was added and the reaction mixturewas stirred at 80° C. for 3 h. LCMS showed completion of debenzoylationand formation of 16. Cooled down to room temperature, methanol wasevaporated, 20 ml of water was added. Product was extracted by ethylacetate (25 ml×2). Combined organic phases was washed with water (25ml), 14% ammonium hydroxide (25 ml), water (25 ml) and brine (25 ml). Itwas dried over sodium sulfate, concentrated and purified by flash columnchromatography (silica gel column, CH₂Cl₂/(90% CH₂Cl₂+9.8% methanol+0.2%NH₄OH)) to obtain 0.60 g (yield, 84%) of 16 as an orange solid. MS (ESI)m/z [M+H]⁺; calcd for C₅₅H₆₄ClFN₇O₉; 1020.4, found 1020.9.

To the solution of 16 (0.20 g, 0.20 mmol) in 6.6 ml of dichloromethane,HCl (2.5 ml of 4N in dioxane, 10 mmol) was added and stirred at roomtemperature for 1 h. LCMS showed complete removal of Boc group. Solventwas removed in vacuo. The residue was dissolved in anhydrous methanol(6.6 ml), bis-boc-1-pyrazolecarboxamide (0.075 g, 0.24 mmol) andN-N-diisopropylethylamine (0.26 g, 2 mmol) were added and stirred atroom temperature for 12 h. LCMS showed completion of guanylation.Solvent was removed, residue was dissolved in 10 ml of trifluoroaceticacid, 10 drops of thioanisole was added and the reaction mixture wasstirred at 55° C. for 5 h. LCMS showed complete removal of Boc and Cbzgroups. The solution was concentrated in vacuo and purified by HPLCusing C₁₈ stationary phase. Desired fractions were concentrated todryness, TFA was exchanged with HCl (6N aq., 10 ml×2 in 15 min interval)and lyophilized to obtain 0.093 g (yield, 63% over 4 steps) of compound23 as yellow solid. ¹H NMR (300 MHz, D₂O): δ8.39 (s, 1H), 7.65 (d, J=5.5Hz, 2H), 7.55 (d, J=5.5 Hz, 2H), 7.42 (d, J=5.5 Hz, 1H), 7.33 (d, J=5.5Hz, 1H), 6.80 (s, 1H), 3.88 (s, br, 1H), 3.76-3.50 (m, 2H), 3.45-3.21(m, 3H), 2.64 (s, br, 2H), 2.28-2.10 (m, 2H), 1.70-1.35 (m, 4H), 1.19(d, J=6.3 Hz, 3H). MS (ESI) m/z [M+H]⁺; calcd for C₃₀H₃₈ClFN₉O; 594.3,found 594.5.

Example 2 Antimicrobial Activity

The compounds of the present disclosure were tested for antimicrobialactivity. These data are presented in Table 2. The Compounds 1-32 wererun against Eschericia colt (E. coli) strain ATCC₂₅₉₂₂ and againstStaphylococcus aureus (S. aureus) 11540 strain using a standardmicrodilution assay to determine minimum inhibitory concentrations(MICs). The data is presented whereby a “+” indicates that the compoundhas an MIC value of 16 micrograms/mL or less and a “−” indicates thatthe compound has an MIC value greater than 16 micrograms/mL. It will berecognized by one skilled in the art that the compounds can be assessedagainst other bacterial organisms and that the presentation of data foractivity against Eschericia colt and Staphylococcus aureus areillustrative and in no way is intended to limit the scope of the presentdisclosure. The compounds of the present disclosure can be assayedagainst a range of other microorganisms depending upon the performanceactivity desired to be gathered. Furthermore, the “+” and “−”representation and the selection of a cutoff value of 16 micrograms/mLis also illustrative and in no way is intended to limit the scope of thepresent disclosure. For example, a “−” is not meant to indicate that thecompound necessarily lacks activity or utility, but rather that its MICvalue against the indicated microorganism is greater than 16micrograms/mL.

TABLE 2 MIC MIC # S. aureus E. coli  1 + −  2 + +  5 + +  6 + +  7 + + 8 + +  9 + + 10 + + 11 + + 12 + + 14 + + 15 + + 16 + + 17 + + 18 + +19 + + 20 + + 21 + + 22 + + 23 + + 24 + + 25 + + 26 + − 27 + + 28 + +29 + + 30 + + 31 + + 32 + + 56 + +

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

Equivalents

The disclosure can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the disclosure described herein. Scope of thedisclosure is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A compound of Formula (I)

or a tautomer or a pharmaceutically acceptable salt of the compound ortautomer, wherein: R₁ is halo; R₂ is halo; R₃ is selected from H, halo,C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1), SR^(a1), S(O)₂R^(b1), and 5- to6-membered heterocycloalkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with a substituent selected from C(O)OR^(a1),C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄ alkoxy isoptionally substituted with C₁₋₄ alkoxy; R₄ is selected from H, C₁₋₆alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionallysubstituted with a substituent selected from OR^(a2), SR^(a2),NR^(c2)R^(d2), and NR^(c2)C(═NR^(e2))NR^(c2)R^(d2); X is selected fromO, NR₅, and CH₂; R₅ is selected from H and C₁₋₄ alkyl; W is selectedfrom CR^(6A)R^(6B) and NR^(6A); Y is N or CR₃; R^(6A) is selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; R^(6B) is H; or R^(6A) and R^(6B)together form an oxo group; or R^(6A) and R₄ together with the carbonatom to which R₄ is attached, the W atom to which R^(6A) is attached andthe X atom connecting W and the carbon atom to which R₄ is attached,form a 5- to 6-membered heterocycloalkyl ring containing 1-3heteroatoms; R₇ is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₅cycloalkyl; each of R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(c2), andR^(d2) is independently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and5- to 6-membered heteroaryl; and R₈ is selected from H, C₁₋₄ alkenyl,C₁₋₄ haloalkyl and C₁₋₄ alkyl optionally substituted with a substituentselected from amino, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-memberedheterocycloalkyl; R₉ is selected from H and halo; and R^(e2) is selectedfrom H and C₁₋₄ alkyl.
 2. A compound of Formula (II)

or a tautomer or a pharmaceutically acceptable salt of the compound ortautomer, wherein: R₁ is halo; R₂ is halo; R₃ is selected from H, halo,C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1), SR^(a1), S(O)₂R^(b1), and 5- to6-membered heterocycloalkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with a substituent selected from C(O)OR^(a1),C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄ alkoxy isoptionally substituted with C₁₋₄ alkoxy; R₄ is selected from H, C₁₋₆alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionallysubstituted with a substituent selected from OR^(a2), SR^(a2),NR^(c2)R^(d2), and NR^(c2)C(═NR^(e2))NR^(c2)R^(d2); X is selected fromO, NR₅, and CH₂; R₅ is selected from H and C₁₋₄ alkyl; W is selectedfrom the CR^(6A)R^(6B) and NR^(6A); Y is N or CR₃; R^(6A) is selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; R^(6B) is H; or R^(6A) andR^(6B) together form an oxo group; or R^(6A) and R₄ together with thecarbon atom to which R₄ is attached, the W atom to which R^(6A) isattached and the X atom connecting W and the carbon atom to which R₄ isattached, form a 5- to 6-membered heterocycloalkyl ring containing 1-3heteroatoms; R₇ is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₅cycloalkyl; each of R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(c2), andR^(d2) is independently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and5- to 6-membered heteroaryl; and R₈ is selected from H, C₁₋₄ alkenyl,C₁₋₄ haloalkyl and C₁₋₄ alkyl optionally substituted with a substituentselected from amino, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-memberedheterocycloalkyl; and R^(c2) is selected from H and C₁₋₄ alkyl.
 3. Thecompound of claim 1 or 2, wherein R₁ is fluoro.
 4. The compound of anyone of claims 1-3, wherein R₂ is chloro.
 5. The compound of any one ofclaims 1-4, wherein Y is CR₃ and R₃ is selected from halo, C₁₋₆ alkyl,NR^(c1)R^(d1), NO₂, OR^(a1), SR^(a1), S(O)₂R^(b1), and 5- to 6-memberedheterocycloalkyl, wherein the C₁₋₆ alkyl is optionally substituted witha substituent selected from C(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄alkoxy, and wherein the C₁₋₄ alkoxy is optionally substituted with C₁₋₄alkoxy.
 6. The compound of any one of claims 1-4, wherein Y is CR₃ andR₃ is selected from H, fluoro, NO₂, methylsulfonyl, methoxy, methylthio,carboxymethyl, methylaminocarbonylmethyl, N-morpholino,(2-methoxyethoxy)methyl, and dimethylamino.
 7. The compound of any oneof claims 1-4, wherein Y is CR₃ and R₃ is selected from fluoro, NO₂,methylsulfonyl, methoxy, methylthio, carboxymethyl,methylaminocarbonylmethyl, N-morpholino, (2-methoxyethoxy)methyl, anddimethylamino.
 8. The compound of any one of claims 1-4, wherein Y isCR₃ and R₃ is H.
 9. The compound of any one of claims 1-8, wherein R₄ isselected from H, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from S(C₁₋₄ alkyl), NR^(c2)R^(d2), andNR^(c2)C(═NR^(e2))NR^(c2)R^(d2).
 10. The compound of any one of claims1-8, wherein R₄ is selected from C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with asubstituent selected from S(C₁₋₄ alkyl), NR^(c2)R^(d2), andNR^(c2)C(═NR^(e2))NR^(c2)R^(d2).
 11. The compound of any one of claims1-8, wherein R₄ is selected from H, methyl, methylthiomethyl,hydroxymethyl, CH₂NH(imidazol-2-yl), guanidinomethyl, ethenyl,CH₂NH(pyridin-2-yl), and aminomethyl.
 12. The compound of any one ofclaims 1-8, wherein R₄ is selected from methyl, methylthiomethyl,hydroxymethyl, CH₂NH(imizado1-2-yl), guanidinomethyl, ethenyl,CH₂NH(pyridin-2-yl), and aminomethyl.
 13. The compound of any one ofclaims 1-8, wherein R₄ is H.
 14. The compound of any one of claims 1-13,wherein X is NR₅.
 15. The compound of any one of claims 1-13, wherein Xis NH.
 16. The compound of any one of claims 1-13, wherein X is O. 17.The compound of any one of claims 1-13, wherein Xis CH₂.
 18. Thecompound of any one of claims 1-13, wherein R₅ is H.
 19. The compound ofany one of claims 1-18, wherein W is CR^(6A)R^(6B).
 20. The compound ofany one of claims 1-18, wherein W is NR^(6A).
 21. The compound of anyone of claims 1-20, wherein R^(6A) is selected from H, methyl,trifluoromethyl, and difluoromethyl.
 22. The compound of any one ofclaims 1-20, wherein R^(6A) and R^(6B) together form an oxo group. 23.The compound of any one of claims 1-22, wherein R^(6A) and R₄ togetherwith the carbon atom to which R₄ is attached, the W atom to which R^(6A)is attached and the X atom connecting W and the carbon atom to which R₄is attached, form a ring of any one of the following formulae:


24. The compound of any one of claims 1-22, wherein R^(6A) and R₄together with the carbon atom to which R₄ is attached, the W atom towhich R^(6A) is attached and the X atom connecting W and the carbon atomto which R₄ is attached, form a ring of formula:

wherein x indicates a point of attachment to the ring containing Y. 25.The compound of any one of claims 1-24, wherein R₇ is selected frommethyl, trifluoromethyl, and cyclopropyl.
 26. The compound of any one ofclaims 1-24, wherein R₇ is methyl.
 27. The compound of claim 26, whereinthe carbon atom to which R₇ is attached is in (S) configuration.
 28. Thecompound of claim 1, wherein R₉ is H.
 29. The compound of claim 1,wherein R₉ is halo.
 30. The compound of claim 29, wherein R₉ isfluorine.
 31. The compound of claim 1, wherein: R₁ is fluoro; R₂ ischloro; Y is CR₃; R₃ is selected from H, halo, C₁₋₆ alkyl,NR^(c1)R^(d1), NO₂, OR^(a1), SR^(a1), S(O)₂R^(b1), and 5- to 6-memberedheterocycloalkyl, wherein the C₁₋₆ alkyl is optionally substituted witha substituent selected from C(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄alkoxy, and wherein the C₁₋₄ alkoxy is optionally substituted with C₁₋₄alkoxy; R₄ is selected from H, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with asubstituent selected from S(C₁₋₄ alkyl), NR^(c2)R^(d2) andNR^(c2)C(═NR^(e2))NR^(c2)R^(d2); X is NR₅; W is CR^(6A)R^(6B); R^(6A) isselected from H, methyl, trifluoromethyl, and difluoromethyl; R₇ isselected from methyl, trifluoromethyl, and cyclopropyl; R₈ is H; and R₉is H.
 32. The compound of claim 1, wherein: R₁ is fluoro; R₂ is chloro;Y is CR_(3;) R₃ is selected from H, fluoro, NO₂, methylsulfonyl,methoxy, methylthio, carboxymethyl, methyl aminocarbonylmethyl,N-morpholino, (2-methoxyethoxy)methyl, and dimethylamino; R₄ is selectedfrom H, methyl, methylthiomethyl, hydroxymethyl, CH₂NH(imidazol-2-yl),guanidinomethyl, ethenyl, CH₂NH(pyridin-2-yl), and aminomethyl; X is NH;W is CR^(6A)R^(6B); R^(6A) is selected from H, methyl, trifluoromethyl,and difluoromethyl; R₇ is selected from methyl, trifluoromethyl, andcyclopropyl; and R₈ is H; and R₉ is H.
 33. The compound of claim 1,wherein: R₁ is fluoro; R₂ is chloro; Y is CR₃; R₃ is H; R₄ is selectedfrom C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl is optionally substituted with a substituent selected fromNR^(c2)R^(d2) and _(NR) ^(c2)C(═NR^(e2))NR^(c2)R^(d2); X is NH; W isCR^(6A)R^(6B); R^(6A) and R^(6B) together form an oxo group; R₇ ismethyl; and R₈ is H; and R₉ is H.
 34. The compound of claim 1, wherein:R₁ is fluoro; R₂ is chloro; Y is CR₃; R₃ is H; X is NH; R₄ is selectedfrom methyl, methylthiomethyl, hydroxymethyl, CH₂NH(imizadol-2-yl),CH₂NH(pyridin-2-yl), guanidinomethyl, ethenyl, and aminomethyl W isCR^(6A)R^(6B); R^(6A) and R^(6B) together form an oxo group; R₇ ismethyl; and R₈ is H; and R₉ is H.
 35. The compound of claim 1, wherein:R₁ is fluoro; R₂ is chloro; Y is CR₃; R₃ is selected from halo, OR^(a1),and SR^(a1); X is O; R₄ is C₁₋₆ alkyl substituted withNR^(c2)C(═NR^(e2))NR^(c2)R^(d2); W is CH²; R₇ is methyl; and R₈ is H;and R₉ is H.
 36. The compound of claim 1, wherein: R₁ is fluoro; R₂ ischloro; Y is CR₃; R₃ is selected from fluoro, methoxy, and methylthio; Xis O; R₄ is guanidinomethyl; W is CH₂; R₇ is methyl; and R₈ is H; and R₉is H.
 37. The compound of claim 1, wherein: R₁ is fluoro; R₂ is chloro;Y is CR₃; R₃ is selected from halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂,OR^(a1), SR^(a1), S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from C(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, andwherein the C₁₋₄ alkoxy is optionally substituted with C₁₋₄ alkoxy;R^(6A) and R₄ together with the carbon atom to which R₄ is attached, theW atom to which R^(6A) is attached and the X atom connecting W and thecarbon atom to which R₄ is attached, form a ring of any one of thefollowing formulae:

R₇ is selected from C₁₋₄ alkyl and C₃₋₅ cycloalkyl; and R₈ is H; and R₉is H.
 38. The compound of claim 1, wherein: R₁ is fluoro; R₂ is chloro;Y is CR₃; R₃ is H; W is CR^(6A)R^(6B) or NR^(6A); R^(6A) and R₄ togetherwith the carbon atom to which R₄ is attached, the W atom to which R^(6A)is attached and the X atom connecting W and the carbon atom to which R₄is attached, form a ring of any one of the following formulae:

R₇ is selected from methyl or cyclopropyl; and R₈ is H; and R₉ is H. 39.The compound of claim 2, wherein: R₁ is fluoro; R₂ is chloro; Y is CR₃;R₃ is selected from H, halo, C₁₋₆ alkyl, NR^(c1)R^(d1), NO₂, OR^(a1),SR^(a1), S(O)₂R^(b1), and 5- to 6-membered heterocycloalkyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromC(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄ alkoxy, and wherein the C₁₋₄alkoxy is optionally substituted with C₁₋₄ alkoxy; R₄ is selected fromH, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl is optionally substituted with a substituent selected from S(C₁₋₄alkyl), NR^(c2)R^(d2) and NR^(c2)C(═NR^(e2))NR^(c2)R^(d2); X is NR₅; Wis CR^(6A)R^(6B); R^(6A) is selected from H, methyl, trifluoromethyl,and difluoromethyl; R₇ is selected from methyl, trifluoromethyl, andcyclopropyl; and R₈ is H.
 40. The compound of claim 2, wherein: R₁ isfluoro; R₂ is chloro; Y is CR₃; R₃ is selected from H, fluoro, NO₂,methylsulfonyl, methoxy, methylthio, carboxymethyl,methylaminocarbonylmethyl, N-morpholino, (2-methoxyethoxy)methyl, anddimethylamino; R₄ is selected from H, methyl, methylthiomethyl,hydroxymethyl, CH₂NH(imidazol-2-yl), guanidinomethyl, ethenyl,CH₂NH(pyridin-2-yl), and aminomethyl; X is NH; W is CR^(6A)R^(6B);R^(6A) is selected from H, methyl, trifluoromethyl, and difluoromethyl;R₇ is selected from methyl, trifluoromethyl, and cyclopropyl; and R₈ isH.
 41. The compound of claim 2, wherein: R₁ is fluoro; R₂ is chloro; Yis CR₃; R₃ is H; R₄ is selected from C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, andC₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with asubstituent selected from NR^(c2)R^(d2) andNR^(c2)C(═NR^(e2))NR^(c2)R^(d2); X is NH; W is CR^(6A)R^(6B); R^(6A) andR^(6B) together form an oxo group; R₇ is methyl; and R₈ is H.
 42. Thecompound of claim 2, wherein: R₁ is fluoro; R₂ is chloro; Y is CR₃; R₃is H; X is NH; R₄ is selected from methyl, methylthiomethyl,hydroxymethyl, CH₂NH(imizadol-2-yl), CH₂NH(pyridin-2-yl),guanidinomethyl, ethenyl, and aminomethyl W is CR^(6A)R^(6B); R^(6A) andR^(6B) together form an oxo group; R₇ is methyl; and R₈ is H.
 43. Thecompound of claim 2, wherein: R₁ is fluoro; R₂ is chloro; Y is CR₃; R₃is selected from halo, OR^(a1), and SR^(a1); X is O; R₄ is C₁₋₆ alkylsubstituted with NR^(c2)C(═NR^(e2))NR^(c2)R^(d2); W is CH₂; R₇ ismethyl; and R₈ is H.
 44. The compound of claim 2, wherein: R₁ is fluoro;R₂ is chloro; Y is CR₃; R₃ is selected from fluoro, methoxy, andmethylthio; X is O; R₄ is guanidinomethyl; W is CH₂; R₇ is methyl; andR₈ is H.
 45. The compound of claim 2, wherein: R₁ is fluoro; R₂ ischloro; Y is CR₃; R₃ is selected from halo, C₁₋₆ alkyl, NR^(c1)R^(d1),NO₂, OR^(a1), SR^(a1), S(O)₂R^(b1), and 5- to 6-memberedheterocycloalkyl, wherein the C₁₋₆ alkyl is optionally substituted witha substituent selected from C(O)OR^(a1), C(O)NR^(c1)R^(d1), and C₁₋₄alkoxy, and wherein the C₁₋₄ alkoxy is optionally substituted with C₁₋₄alkoxy; R^(6A) and R₄ together with the carbon atom to which R₄ isattached, the W atom to which R^(6A) is attached and the X atomconnecting W and the carbon atom to which R₄ is attached, form a ring ofany one of the following formulae:

R₇ is selected from C₁₋₄ alkyl and C₃₋₅ cycloalkyl; and R₈ is H.
 46. Thecompound of claim 2, wherein: R₁ is fluoro; R₂ is chloro; Y is CR₃; R₃is H; W is CR^(6A)R^(6B) or NR^(6A); R^(6A) and R₄ together with thecarbon atom to which R₄ is attached, the W atom to which R^(6A) isattached and the X atom connecting W and the carbon atom to which R₄ isattached, form a ring of any one of the following formulae:

R₇ is selected from methyl or cyclopropyl; and R₈ is H.
 47. The compoundof any one of claims 1-46 having Formula (Ia) or Formula (Ib):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer.
 48. The compound of any one of claims 1-46 havingFormula (Ic):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer.
 49. The compound of any one of claims 1-46 havingFormula (Ic-1);

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer.
 50. The compound of any one of claims 1-46 havingFormula (Id):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer.
 51. The compound of any one of claims 1-46 havingany one of Formulae (Ie)-(Ii):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer.
 52. The compound of claim 1 or 2 selected from anyone of the compounds listed in Table 1, Table 1a, or Table 1b, or atautomer thereof or a pharmaceutically acceptable salt of the compoundor tautomer.
 53. A pharmaceutical composition comprising a compound ofany one of claims 1-52, or a tautomer thereof or a pharmaceuticallyacceptable salt of the compound or tautomer, and a pharmaceuticallyacceptable carrier.
 54. A method of treating a microbial infectioncomprising administering to a subject in need thereof an effectiveamount of a compound of any one of claims 1-52, or a tautomer thereof ora pharmaceutically acceptable salt of the compound or tautomer, or apharmaceutically acceptable composition of claim
 53. 55. A method ofpreventing a microbial infection comprising administering to a subjectin need thereof an effective amount of a compound of any one of claims1-52, or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, or a pharmaceutically acceptable composition ofclaim
 53. 56. A method of reducing the risk of a microbial infectioncomprising administering to a subject in need thereof an effectiveamount of a compound of any one of claims 1-52, or a tautomer thereof ora pharmaceutically acceptable salt of the compound or tautomer, or apharmaceutically acceptable composition of claim
 53. 57. A method ofdelaying the onset of a microbial infection comprising administering toa subject in need thereof an effective amount of a compound of any oneof claims 1-52, or a tautomer thereof or a pharmaceutically acceptablesalt of the compound or tautomer, or a pharmaceutically acceptablecomposition of claim
 53. 58. Use of a compound according to any one ofclaims 1-52, or a tautomer thereof or a pharmaceutically acceptable saltof the compound or tautomer, in the manufacture of a medicament fortreating, preventing, or reducing a microbial infection in a subject.59. A compound according to any one of claims 1-52, or a tautomerthereof or a pharmaceutically acceptable salt of the compound ortautomer, for use in treating, preventing, or reducing a microbialinfection in a subject.